Hsu Lab members Yulia and Sekyu won presentation awards at the 2019 HSCI retreat!
Hsu Lab Publications
All publications are available here.
Featured Publications
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2022. Neurobiology, Stem Cell Biology, and Immunology: An Emerging Triad for Understanding Tissue Homeostasis and Repair. Annual review of cell and developmental biology. 38:419-446. Pubmed: 36201298 DOI:10.1146/annurev-cellbio-120320-032429 Scott-Solomon E, Hsu YC. 2022. Neurobiology, Stem Cell Biology, and Immunology: An Emerging Triad for Understanding Tissue Homeostasis and Repair. Annual review of cell and developmental biology. 38:419-446. Pubmed: 36201298 DOI:10.1146/annurev-cellbio-120320-032429 The peripheral nervous system (PNS) endows animals with the remarkable ability to sense and respond to a dynamic world. Emerging evidence shows the PNS also participates in tissue homeostasis and repair by integrating local changes with organismal and environmental changes. Here, we provide an in-depth summary of findings delineating the diverse roles of peripheral nerves in modulating stem cell behaviors and immune responses under steady-state conditions and in response to injury and duress, with a specific focus on the skin and the hematopoietic system. These examples showcase how elucidating neuro-stem cell and neuro-immune cell interactions provides a conceptual framework that connects tissue biology and local immunity with systemic bodily changes to meet varying demands. They also demonstrate how changes in these interactions can manifest in stress, aging, cancer, and inflammation, as well as how these findings can be harnessed to guide the development of new therapeutics. -
Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SM, Shamsi F, Assaad S, Lin ET, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. 2020. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell. 182(3):578-593.e19. Pubmed: 32679029 DOI:S0092-8674(20)30808-4 Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SM, Shamsi F, Assaad S, Lin ET, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. 2020. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell. 182(3):578-593.e19. Pubmed: 32679029 DOI:S0092-8674(20)30808-4 Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.Copyright © 2020 Elsevier Inc. All rights reserved. -
Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC. 2020. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature. 577(7792):676-681. Pubmed: 31969699 DOI:10.1038/s41586-020-1935-3 Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC. 2020. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature. 577(7792):676-681. Pubmed: 31969699 DOI:10.1038/s41586-020-1935-3 Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism. -
Goldstein JM, Tabebordbar M, Zhu K, Wang LD, Messemer KA, Peacker B, Ashrafi Kakhki S, Gonzalez-Celeiro M, Shwartz Y, Cheng JKW, Xiao R, Barungi T, Albright C, Hsu YC, Vandenberghe LH, Wagers AJ. 2019. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell reports. 27(4):1254-1264.e7. Pubmed: 31018138 DOI:S2211-1247(19)30452-8 Goldstein JM, Tabebordbar M, Zhu K, Wang LD, Messemer KA, Peacker B, Ashrafi Kakhki S, Gonzalez-Celeiro M, Shwartz Y, Cheng JKW, Xiao R, Barungi T, Albright C, Hsu YC, Vandenberghe LH, Wagers AJ. 2019. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell reports. 27(4):1254-1264.e7. Pubmed: 31018138 DOI:S2211-1247(19)30452-8 In vivo delivery of genome-modifying enzymes holds significant promise for therapeutic applications and functional genetic screening. Delivery to endogenous tissue stem cells, which provide an enduring source of cell replacement during homeostasis and regeneration, is of particular interest. Here, we use a sensitive Cre/lox fluorescent reporter system to test the efficiency of genome modification following in vivo transduction by adeno-associated viruses (AAVs) in tissue stem and progenitor cells. We combine immunophenotypic analyses with in vitro and in vivo assays of stem cell function to reveal effective targeting of skeletal muscle satellite cells, mesenchymal progenitors, hematopoietic stem cells, and dermal cell subsets using multiple AAV serotypes. Genome modification rates achieved through this system reached >60%, and modified cells retained key functional properties. This study establishes a powerful platform to genetically alter tissue progenitors within their physiological niche while preserving their native stem cell properties and regulatory interactions.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. -
Zhang B, Hsu YC. 2017. Emerging roles of transit-amplifying cells in tissue regeneration and cancer. Wiley interdisciplinary reviews. Developmental biology. 6(5). Pubmed: 28670819 DOI:10.1002/wdev.282 Zhang B, Hsu YC. 2017. Emerging roles of transit-amplifying cells in tissue regeneration and cancer. Wiley interdisciplinary reviews. Developmental biology. 6(5). Pubmed: 28670819 DOI:10.1002/wdev.282 Most regenerative tissues employ transit-amplifying cells (TACs) that are positioned in between stem cells and differentiated progeny. In a classical hierarchical model, stem cells undergo limited divisions to produce TACs, which then proliferate rapidly to expand the system and produce diverse differentiated cell types. Although TACs are indispensable for generating tissues, they have been largely viewed as a transit point between stem cells and downstream lineages. Studies in the past few years, however, have revealed some fascinating biology and unanticipated functions of TACs. In the hair follicle, recent findings have placed TACs as key players in tissue regeneration by coordinating tissue production, governing stem cell behaviors, and instructing niche remodeling. In the hematopoietic system, rather than being transient, some TACs may participate in long-term hematopoiesis under steady state. Here, we compare and summarize recent discoveries about TACs in the hair follicle and the hematopoietic system. We also discuss how TACs of these two tissues contribute to the formation of cancer. WIREs Dev Biol 2017, 6:e282. doi: 10.1002/wdev.282 For further resources related to this article, please visit the WIREs website.© 2017 Wiley Periodicals, Inc. -
Zhang B, Tsai PC, Gonzalez-Celeiro M, Chung O, Boumard B, Perdigoto CN, Ezhkova E, Hsu YC. 2016. Hair follicles' transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog. Genes & development. 30(20):2325-2338. Pubmed: 27807033 Zhang B, Tsai PC, Gonzalez-Celeiro M, Chung O, Boumard B, Perdigoto CN, Ezhkova E, Hsu YC. 2016. Hair follicles' transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog. Genes & development. 30(20):2325-2338. Pubmed: 27807033 Growth and regeneration of one tissue within an organ compels accommodative changes in the surrounding tissues. However, the molecular nature and operating logic governing these concurrent changes remain poorly defined. The dermal adipose layer expands concomitantly with hair follicle downgrowth, providing a paradigm for studying coordinated changes of surrounding lineages with a regenerating tissue. Here, we discover that hair follicle transit-amplifying cells (HF-TACs) play an essential role in orchestrating dermal adipogenesis through secreting Sonic Hedgehog (SHH). Depletion of Shh from HF-TACs abrogates both dermal adipogenesis and hair follicle growth. Using cell type-specific deletion of Smo, a gene required in SHH-receiving cells, we found that SHH does not act on hair follicles, adipocytes, endothelial cells, and hematopoietic cells for adipogenesis. Instead, SHH acts directly on adipocyte precursors, promoting their proliferation and their expression of a key adipogenic gene, peroxisome proliferator-activated receptor γ (Pparg), to induce dermal adipogenesis. Our study therefore uncovers a critical role for TACs in orchestrating the generation of both their own progeny and a neighboring lineage to achieve concomitant tissue production across lineages.© 2016 Zhang et al.; Published by Cold Spring Harbor Laboratory Press. -
Perdigoto CN, Dauber KL, Bar C, Tsai PC, Valdes VJ, Cohen I, Santoriello FJ, Zhao D, Zheng D, Hsu YC, Ezhkova E. 2016. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. PLoS genetics. 12(7):e1006151. Pubmed: 27414999 DOI:10.1371/journal.pgen.1006151 Perdigoto CN, Dauber KL, Bar C, Tsai PC, Valdes VJ, Cohen I, Santoriello FJ, Zhao D, Zheng D, Hsu YC, Ezhkova E. 2016. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. PLoS genetics. 12(7):e1006151. Pubmed: 27414999 DOI:10.1371/journal.pgen.1006151 An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures. -
Gonzalez-Celeiro M, Zhang B, Hsu YC. 2016. Fate by Chance, not by Choice: Epidermal Stem Cells Go Live. Cell stem cell. 19(1):8-10. Pubmed: 27392221 DOI:S1934-5909(16)30160-6 Gonzalez-Celeiro M, Zhang B, Hsu YC. 2016. Fate by Chance, not by Choice: Epidermal Stem Cells Go Live. Cell stem cell. 19(1):8-10. Pubmed: 27392221 DOI:S1934-5909(16)30160-6 The skin epidermis is constantly renewed by epidermal stem cells. In a recent Science paper, Rompolas et al. utilize live imaging to track epidermal stem cells over their lifetimes. Their findings provide new insights into epidermal stem cell behaviors and unravel how newly generated cells are integrated into pre-existing tissues.Copyright © 2016 Elsevier Inc. All rights reserved. -
Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J. 2016. Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell stem cell. 19(2):217-231. Pubmed: 27320041 DOI:S1934-5909(16)30096-0 Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J. 2016. Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell stem cell. 19(2):217-231. Pubmed: 27320041 DOI:S1934-5909(16)30096-0 Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD signaling inhibition in a feeder-free culture system, we have been able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium physiologically responsive to clinically relevant drugs, such as CFTR modulators. This approach is effective for the clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers and therefore may be broadly applicable for modeling of epithelia.Copyright © 2016 Elsevier Inc. All rights reserved. -
Hsu YC, Li L, Fuchs E. 2014. Emerging interactions between skin stem cells and their niches. Nature medicine. 20(8):847-56. Pubmed: 25100530 DOI:10.1038/nm.3643 Hsu YC, Li L, Fuchs E. 2014. Emerging interactions between skin stem cells and their niches. Nature medicine. 20(8):847-56. Pubmed: 25100530 DOI:10.1038/nm.3643 The skin protects mammals from insults, infection and dehydration and enables thermoregulation and sensory perception. Various skin-resident cells carry out these diverse functions. Constant turnover of cells and healing upon injury necessitate multiple reservoirs of stem cells. Thus, the skin provides a model for studying interactions between stem cells and their microenvironments, or niches. Advances in genetic and imaging tools have brought new findings about the lineage relationships between skin stem cells and their progeny and about the mutual influences between skin stem cells and their niches. Such knowledge may offer novel avenues for therapeutics and regenerative medicine. -
Hsu YC, Li L, Fuchs E. 2014. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell. 157(4):935-49. Pubmed: 24813615 DOI:S0092-8674(14)00416-4 Hsu YC, Li L, Fuchs E. 2014. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell. 157(4):935-49. Pubmed: 24813615 DOI:S0092-8674(14)00416-4 Transit-amplifying cells (TACs) are an early intermediate in tissue regeneration. Here, using hair follicles (HFs) as a paradigm, we show that emerging TACs constitute a signaling center that orchestrates tissue growth. Whereas primed stem cells (SCs) generate TACs, quiescent SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). TAC generation is independent of autocrine SHH, but the TAC pool wanes if they can't produce SHH. We trace this paradox to two direct actions of SHH: promoting quiescent-SC proliferation and regulating dermal factors that stoke TAC expansion. Ingrained within quiescent SCs' special sensitivity to SHH signaling is their high expression of GAS1. Without sufficient input from quiescent SCs, replenishment of primed SCs for the next hair cycle is compromised, delaying regeneration and eventually leading to regeneration failure. Our findings unveil TACs as transient but indispensable integrators of SC niche components and reveal an intriguing interdependency of primed and quiescent SC populations on tissue regeneration.Copyright © 2014 Elsevier Inc. All rights reserved. -
Hsu YC, Pasolli HA, Fuchs E. 2011. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell. 144(1):92-105. Pubmed: 21215372 DOI:10.1016/j.cell.2010.11.049 Hsu YC, Pasolli HA, Fuchs E. 2011. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell. 144(1):92-105. Pubmed: 21215372 DOI:10.1016/j.cell.2010.11.049 Here, we exploit the hair follicle to define the point at which stem cells (SCs) become irreversibly committed along a differentiation lineage. Employing histone and nucleotide double-pulse-chase and lineage tracing, we show that the early SC descendents en route to becoming transit-amplifying cells retain stemness and slow-cycling properties and home back to the bulge niche when hair growth stops. These become the primary SCs for the next hair cycle, whereas initial bulge SCs become reserves for injury. Proliferating descendents further en route irreversibly lose their stemness, although they retain many SC markers and survive, unlike their transit-amplifying progeny. Remarkably, these progeny also home back to the bulge. Combining purification and gene expression analysis with differential ablation and functional experiments, we define critical functions for these non-SC niche residents and unveil the intriguing concept that an irreversibly committed cell in an SC lineage can become an essential contributor to the niche microenvironment.Copyright © 2011 Elsevier Inc. All rights reserved.
All Publications
2022
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Scott-Solomon E, Hsu YC. 2022. Neurobiology, Stem Cell Biology, and Immunology: An Emerging Triad for Understanding Tissue Homeostasis and Repair. Annual review of cell and developmental biology. 38:419-446. Pubmed: 36201298 DOI:10.1146/annurev-cellbio-120320-032429 Scott-Solomon E, Hsu YC. 2022. Neurobiology, Stem Cell Biology, and Immunology: An Emerging Triad for Understanding Tissue Homeostasis and Repair. Annual review of cell and developmental biology. 38:419-446. Pubmed: 36201298 DOI:10.1146/annurev-cellbio-120320-032429 The peripheral nervous system (PNS) endows animals with the remarkable ability to sense and respond to a dynamic world. Emerging evidence shows the PNS also participates in tissue homeostasis and repair by integrating local changes with organismal and environmental changes. Here, we provide an in-depth summary of findings delineating the diverse roles of peripheral nerves in modulating stem cell behaviors and immune responses under steady-state conditions and in response to injury and duress, with a specific focus on the skin and the hematopoietic system. These examples showcase how elucidating neuro-stem cell and neuro-immune cell interactions provides a conceptual framework that connects tissue biology and local immunity with systemic bodily changes to meet varying demands. They also demonstrate how changes in these interactions can manifest in stress, aging, cancer, and inflammation, as well as how these findings can be harnessed to guide the development of new therapeutics. 2020
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Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC. 2020. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature. 577(7792):676-681. Pubmed: 31969699 DOI:10.1038/s41586-020-1935-3 Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC. 2020. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature. 577(7792):676-681. Pubmed: 31969699 DOI:10.1038/s41586-020-1935-3 Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism. -
Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SM, Shamsi F, Assaad S, Lin ET, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. 2020. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell. 182(3):578-593.e19. Pubmed: 32679029 DOI:S0092-8674(20)30808-4 Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SM, Shamsi F, Assaad S, Lin ET, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. 2020. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell. 182(3):578-593.e19. Pubmed: 32679029 DOI:S0092-8674(20)30808-4 Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.Copyright © 2020 Elsevier Inc. All rights reserved. 2019
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Huang WY, Lin ET, Hsu YC, Lin SJ. 2019. Anagen hair follicle repair: Timely regenerative attempts from plastic extra-bulge epithelial cells. Experimental dermatology. 28(4):406-412. Pubmed: 30664259 DOI:10.1111/exd.13889 Huang WY, Lin ET, Hsu YC, Lin SJ. 2019. Anagen hair follicle repair: Timely regenerative attempts from plastic extra-bulge epithelial cells. Experimental dermatology. 28(4):406-412. Pubmed: 30664259 DOI:10.1111/exd.13889 Anagen hair follicle repair (AHFR) is the regenerative scheme activated to restore the structure and hair growth following injuries to anagen hair follicles. Compared with telogen-to-anagen regeneration and hair follicle neogenesis, AHFR is a clinically important, yet relatively unexplored regenerative feature of hair follicles. Due to their highly proliferative character, germinative cells and matrix cells within hair bulbs are highly susceptible to injuries, such as chemotherapy and radiotherapy. Clinical and experimental observations suggest that damaged anagen hair follicles are able to repair themselves to resume anagen growth, bypassing premature catagen/telogen entry. Mechanistically, extra-bulge epithelial cells in the outer root sheath and the lower proximal cup are quickly mobilized for regeneration. These cells acquire stem cell-like properties, exhibiting high plasticity by breaking lineage restriction to regenerate all cell types in the lower segment of anagen hair follicles. Facilitating extra-bulge epithelial cells' mobilization ameliorates hair loss from chemo- and radiotherapy. On the other hand, quiescent bulge stem cells can also be activated, but only after more severe injuries and with slower activation dynamics. They show limited plasticity and regenerate part of the outer root sheath only. The dysrhythmic activation might render bulge stem cells susceptible to concomitant injuries due to their exit from quiescence.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. -
Goldstein JM, Tabebordbar M, Zhu K, Wang LD, Messemer KA, Peacker B, Ashrafi Kakhki S, Gonzalez-Celeiro M, Shwartz Y, Cheng JKW, Xiao R, Barungi T, Albright C, Hsu YC, Vandenberghe LH, Wagers AJ. 2019. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell reports. 27(4):1254-1264.e7. Pubmed: 31018138 DOI:S2211-1247(19)30452-8 Goldstein JM, Tabebordbar M, Zhu K, Wang LD, Messemer KA, Peacker B, Ashrafi Kakhki S, Gonzalez-Celeiro M, Shwartz Y, Cheng JKW, Xiao R, Barungi T, Albright C, Hsu YC, Vandenberghe LH, Wagers AJ. 2019. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell reports. 27(4):1254-1264.e7. Pubmed: 31018138 DOI:S2211-1247(19)30452-8 In vivo delivery of genome-modifying enzymes holds significant promise for therapeutic applications and functional genetic screening. Delivery to endogenous tissue stem cells, which provide an enduring source of cell replacement during homeostasis and regeneration, is of particular interest. Here, we use a sensitive Cre/lox fluorescent reporter system to test the efficiency of genome modification following in vivo transduction by adeno-associated viruses (AAVs) in tissue stem and progenitor cells. We combine immunophenotypic analyses with in vitro and in vivo assays of stem cell function to reveal effective targeting of skeletal muscle satellite cells, mesenchymal progenitors, hematopoietic stem cells, and dermal cell subsets using multiple AAV serotypes. Genome modification rates achieved through this system reached >60%, and modified cells retained key functional properties. This study establishes a powerful platform to genetically alter tissue progenitors within their physiological niche while preserving their native stem cell properties and regulatory interactions.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. 2018
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Nguyen MB, Cohen I, Kumar V, Xu Z, Bar C, Dauber-Decker KL, Tsai PC, Marangoni P, Klein OD, Hsu YC, Chen T, Mikkola ML, Ezhkova E. 2018. FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells. Nature communications. 9(1):2333. Pubmed: 29899403 DOI:10.1038/s41467-018-04399-y Nguyen MB, Cohen I, Kumar V, Xu Z, Bar C, Dauber-Decker KL, Tsai PC, Marangoni P, Klein OD, Hsu YC, Chen T, Mikkola ML, Ezhkova E. 2018. FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells. Nature communications. 9(1):2333. Pubmed: 29899403 DOI:10.1038/s41467-018-04399-y Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification. 2017
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Zhang B, Hsu YC. 2017. Emerging roles of transit-amplifying cells in tissue regeneration and cancer. Wiley interdisciplinary reviews. Developmental biology. 6(5). Pubmed: 28670819 DOI:10.1002/wdev.282 Zhang B, Hsu YC. 2017. Emerging roles of transit-amplifying cells in tissue regeneration and cancer. Wiley interdisciplinary reviews. Developmental biology. 6(5). Pubmed: 28670819 DOI:10.1002/wdev.282 Most regenerative tissues employ transit-amplifying cells (TACs) that are positioned in between stem cells and differentiated progeny. In a classical hierarchical model, stem cells undergo limited divisions to produce TACs, which then proliferate rapidly to expand the system and produce diverse differentiated cell types. Although TACs are indispensable for generating tissues, they have been largely viewed as a transit point between stem cells and downstream lineages. Studies in the past few years, however, have revealed some fascinating biology and unanticipated functions of TACs. In the hair follicle, recent findings have placed TACs as key players in tissue regeneration by coordinating tissue production, governing stem cell behaviors, and instructing niche remodeling. In the hematopoietic system, rather than being transient, some TACs may participate in long-term hematopoiesis under steady state. Here, we compare and summarize recent discoveries about TACs in the hair follicle and the hematopoietic system. We also discuss how TACs of these two tissues contribute to the formation of cancer. WIREs Dev Biol 2017, 6:e282. doi: 10.1002/wdev.282 For further resources related to this article, please visit the WIREs website.© 2017 Wiley Periodicals, Inc. 2016
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Perdigoto CN, Dauber KL, Bar C, Tsai PC, Valdes VJ, Cohen I, Santoriello FJ, Zhao D, Zheng D, Hsu YC, Ezhkova E. 2016. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. PLoS genetics. 12(7):e1006151. Pubmed: 27414999 DOI:10.1371/journal.pgen.1006151 Perdigoto CN, Dauber KL, Bar C, Tsai PC, Valdes VJ, Cohen I, Santoriello FJ, Zhao D, Zheng D, Hsu YC, Ezhkova E. 2016. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development. PLoS genetics. 12(7):e1006151. Pubmed: 27414999 DOI:10.1371/journal.pgen.1006151 An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures. -
Le TP, Vuong LT, Kim AR, Hsu YC, Choi KW. 2016. 14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila. Nature communications. 7:11501. Pubmed: 27151460 DOI:10.1038/ncomms11501 Le TP, Vuong LT, Kim AR, Hsu YC, Choi KW. 2016. 14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila. Nature communications. 7:11501. Pubmed: 27151460 DOI:10.1038/ncomms11501 14-3-3 family proteins regulate multiple signalling pathways. Understanding biological functions of 14-3-3 proteins has been limited by the functional redundancy of conserved isotypes. Here we provide evidence that 14-3-3 proteins regulate two interacting components of Tor signalling in Drosophila, translationally controlled tumour protein (Tctp) and Rheb GTPase. Single knockdown of 14-3-3ɛ or 14-3-3ζ isoform does not show obvious defects in organ development but causes synergistic genetic interaction with Tctp and Rheb to impair tissue growth. 14-3-3 proteins physically interact with Tctp and Rheb. Knockdown of both 14-3-3 isoforms abolishes the binding between Tctp and Rheb, disrupting organ development. Depletion of 14-3-3s also reduces the level of phosphorylated S6 kinase, phosphorylated Thor/4E-BP and cyclin E (CycE). Growth defects from knockdown of 14-3-3 and Tctp are suppressed by CycE overexpression. This study suggests a novel mechanism of Tor regulation mediated by 14-3-3 interaction with Tctp and Rheb. -
Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J. 2016. Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell stem cell. 19(2):217-231. Pubmed: 27320041 DOI:S1934-5909(16)30096-0 Mou H, Vinarsky V, Tata PR, Brazauskas K, Choi SH, Crooke AK, Zhang B, Solomon GM, Turner B, Bihler H, Harrington J, Lapey A, Channick C, Keyes C, Freund A, Artandi S, Mense M, Rowe S, Engelhardt JF, Hsu YC, Rajagopal J. 2016. Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell stem cell. 19(2):217-231. Pubmed: 27320041 DOI:S1934-5909(16)30096-0 Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD signaling inhibition in a feeder-free culture system, we have been able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium physiologically responsive to clinically relevant drugs, such as CFTR modulators. This approach is effective for the clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers and therefore may be broadly applicable for modeling of epithelia.Copyright © 2016 Elsevier Inc. All rights reserved. -
Gonzalez-Celeiro M, Zhang B, Hsu YC. 2016. Fate by Chance, not by Choice: Epidermal Stem Cells Go Live. Cell stem cell. 19(1):8-10. Pubmed: 27392221 DOI:S1934-5909(16)30160-6 Gonzalez-Celeiro M, Zhang B, Hsu YC. 2016. Fate by Chance, not by Choice: Epidermal Stem Cells Go Live. Cell stem cell. 19(1):8-10. Pubmed: 27392221 DOI:S1934-5909(16)30160-6 The skin epidermis is constantly renewed by epidermal stem cells. In a recent Science paper, Rompolas et al. utilize live imaging to track epidermal stem cells over their lifetimes. Their findings provide new insights into epidermal stem cell behaviors and unravel how newly generated cells are integrated into pre-existing tissues.Copyright © 2016 Elsevier Inc. All rights reserved. -
Zhang B, Tsai PC, Gonzalez-Celeiro M, Chung O, Boumard B, Perdigoto CN, Ezhkova E, Hsu YC. 2016. Hair follicles' transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog. Genes & development. 30(20):2325-2338. Pubmed: 27807033 Zhang B, Tsai PC, Gonzalez-Celeiro M, Chung O, Boumard B, Perdigoto CN, Ezhkova E, Hsu YC. 2016. Hair follicles' transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog. Genes & development. 30(20):2325-2338. Pubmed: 27807033 Growth and regeneration of one tissue within an organ compels accommodative changes in the surrounding tissues. However, the molecular nature and operating logic governing these concurrent changes remain poorly defined. The dermal adipose layer expands concomitantly with hair follicle downgrowth, providing a paradigm for studying coordinated changes of surrounding lineages with a regenerating tissue. Here, we discover that hair follicle transit-amplifying cells (HF-TACs) play an essential role in orchestrating dermal adipogenesis through secreting Sonic Hedgehog (SHH). Depletion of Shh from HF-TACs abrogates both dermal adipogenesis and hair follicle growth. Using cell type-specific deletion of Smo, a gene required in SHH-receiving cells, we found that SHH does not act on hair follicles, adipocytes, endothelial cells, and hematopoietic cells for adipogenesis. Instead, SHH acts directly on adipocyte precursors, promoting their proliferation and their expression of a key adipogenic gene, peroxisome proliferator-activated receptor γ (Pparg), to induce dermal adipogenesis. Our study therefore uncovers a critical role for TACs in orchestrating the generation of both their own progeny and a neighboring lineage to achieve concomitant tissue production across lineages.© 2016 Zhang et al.; Published by Cold Spring Harbor Laboratory Press. 2015
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Smith KA, Arlotta P, Watt FM, Solomon SL. 2015. Seven actionable strategies for advancing women in science, engineering, and medicine. Cell stem cell. 16(3):221-4. Pubmed: 25748929 DOI:S1934-5909(15)00068-5 Smith KA, Arlotta P, Watt FM, Solomon SL. 2015. Seven actionable strategies for advancing women in science, engineering, and medicine. Cell stem cell. 16(3):221-4. Pubmed: 25748929 DOI:S1934-5909(15)00068-5 Achieving gender equality in science will require devising and implementing strategies to overcome the political, administrative, financial, and cultural challenges that exist in the current environment. In this forum, we propose an initial shortlist of recommendations to promote gender equality in science and stimulate future efforts to level the field.Copyright © 2015 Elsevier Inc. All rights reserved. -
Hsu YC. 2015. Theory and Practice of Lineage Tracing. Stem cells (Dayton, Ohio). 33(11):3197-204. Pubmed: 26284340 DOI:10.1002/stem.2123 Hsu YC. 2015. Theory and Practice of Lineage Tracing. Stem cells (Dayton, Ohio). 33(11):3197-204. Pubmed: 26284340 DOI:10.1002/stem.2123 Lineage tracing is a method that delineates all progeny produced by a single cell or a group of cells. The possibility of performing lineage tracing initiated the field of Developmental Biology and continues to revolutionize Stem Cell Biology. Here, I introduce the principles behind a successful lineage-tracing experiment. In addition, I summarize and compare different methods for conducting lineage tracing and provide examples of how these strategies can be implemented to answer fundamental questions in development and regeneration. The advantages and limitations of each method are also discussed.© 2015 AlphaMed Press. 2014
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Hsu YC, Li L, Fuchs E. 2014. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell. 157(4):935-49. Pubmed: 24813615 DOI:S0092-8674(14)00416-4 Hsu YC, Li L, Fuchs E. 2014. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell. 157(4):935-49. Pubmed: 24813615 DOI:S0092-8674(14)00416-4 Transit-amplifying cells (TACs) are an early intermediate in tissue regeneration. Here, using hair follicles (HFs) as a paradigm, we show that emerging TACs constitute a signaling center that orchestrates tissue growth. Whereas primed stem cells (SCs) generate TACs, quiescent SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). TAC generation is independent of autocrine SHH, but the TAC pool wanes if they can't produce SHH. We trace this paradox to two direct actions of SHH: promoting quiescent-SC proliferation and regulating dermal factors that stoke TAC expansion. Ingrained within quiescent SCs' special sensitivity to SHH signaling is their high expression of GAS1. Without sufficient input from quiescent SCs, replenishment of primed SCs for the next hair cycle is compromised, delaying regeneration and eventually leading to regeneration failure. Our findings unveil TACs as transient but indispensable integrators of SC niche components and reveal an intriguing interdependency of primed and quiescent SC populations on tissue regeneration.Copyright © 2014 Elsevier Inc. All rights reserved. -
Hsu YC, Li L, Fuchs E. 2014. Emerging interactions between skin stem cells and their niches. Nature medicine. 20(8):847-56. Pubmed: 25100530 DOI:10.1038/nm.3643 Hsu YC, Li L, Fuchs E. 2014. Emerging interactions between skin stem cells and their niches. Nature medicine. 20(8):847-56. Pubmed: 25100530 DOI:10.1038/nm.3643 The skin protects mammals from insults, infection and dehydration and enables thermoregulation and sensory perception. Various skin-resident cells carry out these diverse functions. Constant turnover of cells and healing upon injury necessitate multiple reservoirs of stem cells. Thus, the skin provides a model for studying interactions between stem cells and their microenvironments, or niches. Advances in genetic and imaging tools have brought new findings about the lineage relationships between skin stem cells and their progeny and about the mutual influences between skin stem cells and their niches. Such knowledge may offer novel avenues for therapeutics and regenerative medicine. 2012
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Hsu YC, Fuchs E. 2012. A family business: stem cell progeny join the niche to regulate homeostasis. Nature reviews. Molecular cell biology. 13(2):103-14. Pubmed: 22266760 DOI:10.1038/nrm3272 Hsu YC, Fuchs E. 2012. A family business: stem cell progeny join the niche to regulate homeostasis. Nature reviews. Molecular cell biology. 13(2):103-14. Pubmed: 22266760 DOI:10.1038/nrm3272 Stem cell niches, the discrete microenvironments in which the stem cells reside, play a dominant part in regulating stem cell activity and behaviours. Recent studies suggest that committed stem cell progeny become indispensable components of the niche in a wide range of stem cell systems. These unexpected niche inhabitants provide versatile feedback signals to their stem cell parents. Together with other heterologous cell types that constitute the niche, they contribute to the dynamics of the microenvironment. As progeny are often located in close proximity to stem cell niches, similar feedback regulations may be the underlying principles shared by different stem cell systems. 2011
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Hsu YC, Pasolli HA, Fuchs E. 2011. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell. 144(1):92-105. Pubmed: 21215372 DOI:10.1016/j.cell.2010.11.049 Hsu YC, Pasolli HA, Fuchs E. 2011. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell. 144(1):92-105. Pubmed: 21215372 DOI:10.1016/j.cell.2010.11.049 Here, we exploit the hair follicle to define the point at which stem cells (SCs) become irreversibly committed along a differentiation lineage. Employing histone and nucleotide double-pulse-chase and lineage tracing, we show that the early SC descendents en route to becoming transit-amplifying cells retain stemness and slow-cycling properties and home back to the bulge niche when hair growth stops. These become the primary SCs for the next hair cycle, whereas initial bulge SCs become reserves for injury. Proliferating descendents further en route irreversibly lose their stemness, although they retain many SC markers and survive, unlike their transit-amplifying progeny. Remarkably, these progeny also home back to the bulge. Combining purification and gene expression analysis with differential ablation and functional experiments, we define critical functions for these non-SC niche residents and unveil the intriguing concept that an irreversibly committed cell in an SC lineage can become an essential contributor to the niche microenvironment.Copyright © 2011 Elsevier Inc. All rights reserved. 2008
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Lim J, Jafar-Nejad H, Hsu YC, Choi KW. 2008. Novel function of the class I bHLH protein Daughterless in the negative regulation of proneural gene expression in the Drosophila eye. EMBO reports. 9(11):1128-33. Pubmed: 18758436 DOI:10.1038/embor.2008.166 Lim J, Jafar-Nejad H, Hsu YC, Choi KW. 2008. Novel function of the class I bHLH protein Daughterless in the negative regulation of proneural gene expression in the Drosophila eye. EMBO reports. 9(11):1128-33. Pubmed: 18758436 DOI:10.1038/embor.2008.166 Two types of basic helix-loop-helix (bHLH) family transcription factor have functions in neurogenesis. Class II bHLH proteins are expressed in tissue-specific patterns, whereas class I proteins are broadly expressed as general cofactors for class II proteins. Here, we show that the Drosophila class I factor Daughterless (Da) is upregulated by Hedgehog (Hh) and Decapentaplegic (Dpp) signalling during retinal neurogenesis. Our data suggest that Da is accumulated in the cells surrounding the neuronal precursor cells to repress the proneural gene atonal (ato), thereby generating a single R8 neuron from each proneural cluster. Upregulation of Da depends on Notch signalling, and, in turn, induces the expression of the Enhancer-of-split proteins for the repression of ato. We propose that the dual functions of Da--as a proneural and as an anti-proneural factor--are crucial for initial neural patterning in the eye. 2007
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Choi KW, Hsu YC. 2007. To cease or to proliferate: new insights into TCTP function from a Drosophila study. Cell adhesion & migration. 1(3):129-30. Pubmed: 19262129 Choi KW, Hsu YC. 2007. To cease or to proliferate: new insights into TCTP function from a Drosophila study. Cell adhesion & migration. 1(3):129-30. Pubmed: 19262129 Tor (target of rapamycin) pathway underlies a major signaling mechanism for controlling cell growth and proliferation.(1) Rheb (Ras homolog enriched in brain) is a small GTPase in the Tor pathway.(2-4) Similar to other small GTPases, Rheb cycles between a GTP-bound active state and a GDP-bound inactive state. TSC2 (tuberous sclerosis complex 2), a gene mutated in an autosomal dominant disease tuberous sclerosis, was shown to be the Rheb-GAP (GTPase activating protein).(5,6) However, a guanine nucleotide exchange factor (GEF) for Rheb had been missing. Human TCTP (translationally controlled tumor protein) has been implicated in cancer, but its function in vivo has not been clearly elucidated. Recently we reported a molecular genetic characterization of TCTP function in Drosophila.(7) Drosophila TCTP (dTCTP) displays GEF activity to Rheb and is essential for Rheb activation in organ growth. Thus, our study provides a tight linkage of dTCTP to the Rheb-TOR pathway. In this addendum, we will briefly overview our findings and discuss our perspectives for future research on TCTP. -
Hsu YC, Chern JJ, Cai Y, Liu M, Choi KW. 2007. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature. 445(7129):785-8. Pubmed: 17301792 Hsu YC, Chern JJ, Cai Y, Liu M, Choi KW. 2007. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature. 445(7129):785-8. Pubmed: 17301792 Cellular growth and proliferation are coordinated during organogenesis. Misregulation of these processes leads to pathological conditions such as cancer. Tuberous sclerosis (TSC) is a benign tumour syndrome caused by mutations in either TSC1 or TSC2 tumour suppressor genes. Studies in Drosophila and other organisms have identified TSC signalling as a conserved pathway for growth control. Activation of the TSC pathway is mediated by Rheb (Ras homologue enriched in brain), a Ras superfamily GTPase. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity. However, molecules required for positive regulation of Rheb have not been identified. Here we show that a conserved protein, translationally controlled tumour protein (TCTP), is an essential new component of the TSC-Rheb pathway. Reducing Drosophila TCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimics Drosophila Rheb (dRheb) mutant phenotypes. dTCTP is genetically epistatic to Tsc1 and dRheb, but acts upstream of dS6k, a downstream target of dRheb. dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro. Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescue dTCTP mutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator of Rheb and a potential therapeutic target for TSC disease. -
Lim J, Lee OK, Hsu YC, Singh A, Choi KW. 2007. Drosophila TRAP230/240 are essential coactivators for Atonal in retinal neurogenesis. Developmental biology. 308(2):322-30. Pubmed: 17585897 Lim J, Lee OK, Hsu YC, Singh A, Choi KW. 2007. Drosophila TRAP230/240 are essential coactivators for Atonal in retinal neurogenesis. Developmental biology. 308(2):322-30. Pubmed: 17585897 The TRAP (thyroid hormone receptor associated proteins)/Mediator complex serves as a transcriptional coactivator. In Drosophila, Kohtalo (Kto) and Skuld (Skd), homologs of TRAP subunits, TRAP230 and TRAP240, respectively, are necessary for eye development. However, the transcriptional activators that require Kto and Skd have not been identified. Here we provide evidence that Kto and Skd are essential for the function of transcription factor Atonal (Ato) in spatial patterning of proneural clusters in the morphogenetic furrow. In the absence of Kto/Skd, Ato fails to induce its inhibitory target events such as EGFR signaling and Scabrous expression that result in ectopic Ato expression in the space between proneural groups. Kto/Skd are also required for positive Ato functions to induce Ato targets such as Ato itself and Senseless within the proneural clusters. We also show that Skd forms a protein complex with Ato in vivo. These data suggest that Kto/Skd act as essential coactivators for Ato expression during early retinal neurogenesis. 2005
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Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB, Krogan N, Cagney G, Mai D, Greenblatt J, Boone C, Emili A, Houry WA. 2005. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell. 120(5):715-27. Pubmed: 15766533 Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB, Krogan N, Cagney G, Mai D, Greenblatt J, Boone C, Emili A, Houry WA. 2005. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell. 120(5):715-27. Pubmed: 15766533 Physical, genetic, and chemical-genetic interactions centered on the conserved chaperone Hsp90 were mapped at high resolution in yeast using systematic proteomic and genomic methods. Physical interactions were identified using genome-wide two hybrid screens combined with large-scale affinity purification of Hsp90-containing protein complexes. Genetic interactions were uncovered using synthetic genetic array technology and by a microarray-based chemical-genetic screen of a set of about 4700 viable yeast gene deletion mutants for hypersensitivity to the Hsp90 inhibitor geldanamycin. An extended network, consisting of 198 putative physical interactions and 451 putative genetic and chemical-genetic interactions, was found to connect Hsp90 to cofactors and substrates involved in a wide range of cellular functions. Two novel Hsp90 cofactors, Tah1 (YCR060W) and Pih1 (YHR034C), were also identified. These cofactors interact physically and functionally with the conserved AAA(+)-type DNA helicases Rvb1/Rvb2, which are key components of several chromatin remodeling factors, thereby linking Hsp90 to epigenetic gene regulation.