Macklis Laboratory

Welcome to the Macklis Lab!

Our laboratory is directed toward both 1) understanding molecular controls and mechanisms over neuron sub-type development, diversity, axon guidance-circuit formation, and degeneration in the cerebral cortex (e.g. corticospinal motor neurons - CSMN - in motor neuron disease - ALS, HSPs, and PLS; corticostriatal projection neurons – CStrPN - in Huntington’s disease – HD – and related corticobasal degeneration - CBD), and 2) applying developmental controls toward both brain and spinal cord regeneration (e.g. corticospinal motor neuron (CSMN) circuitry that degenerates in ALS and other “upper motor neuron” degenerative diseases, and whose injury is central to loss of motor function in spinal cord injury) and directed differentiation for in vitro therapeutic and mechanistic screening.

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Research

The lab focuses on neocortical projection neuron development and sub-type specification; neural progenitor / “stem cell” biology; induction of adult neurogenesis (the birth of new neurons); subtype-specific axonal growth cone biology; and directed neuronal subtype differentiation via molecular manipulation of neural progenitors and pluripotent cells (ES/iPS). The same biology informs understanding of neuronal subtype specificity of vulnerability of human neurodegenerative and developmental diseases, in particular ALS / motor neuron disease, HSPs, PLS, Huntington's disease, autism spectrum disorders (ASD), and Rett syndrome and ACC in particular of ASDs.

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1) Development

  • Corticofugal projection neurons
  • Callosal Projection Neurons
  • Neural/Neuronal subtype specification

2) Development and Regeneration

  • Neurogenesis by endogeneous precursors
  • Integration of transplantated neuronal precursors into complex circuitry
  • Extrinsic factors supporting cortical projection neurons
  • Directed differentiation of embryonic stem cells to cortical-like neurons
  • Degeneration and dysgenesis of neocortical subtypes

1) Development: Understanding molecular controls over neuron sub-type specification and development in the cerebral cortex

Relevant reviews:

Custo Greig L, Woodworth MB, Galazo MJ, Padmanabhan H, Macklis JD. Molecular logic of neocortical projection neuron specification, development and diversity. Nat Rev Neurosci. 2013 Nov;14(11):755-69.

MacDonald JL, Fame RM, Azim E, Shnider SJ, Molyneaux BJ, Arlotta P, Macklis JD. Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS. Rubenstein J, Rakic P, editors. Amsterdam: Elsevier; 2013. Specification of Cortical Projection Neurons; p.475-502. 992p.

Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci. 2007 Jun;8(6):427-37.

Corticofugal projection neurons

(Fame, TINS, 2011)

Czupryn A, Zhou YD, Chen X, McNay D, Anderson MP, Flier JS, Macklis JD. Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice. Science. 2011 Nov 25;334(6059):1133-7.

Tomassy GS, De Leonibus E, Jabaudon D, Lodato S, Alfano C, Mele A, Macklis JD, Studer M. Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3576-81.

Joshi PS, Molyneaux BJ, Feng L, Xie X, Macklis JD, Gan L. Bhlhb5 regulates the postmitotic acquisition of area identities in layers II-V of the developing neocortex. Neuron. 2008 Oct 23;60(2):258-72.

Lai T, Jabaudon D, Molyneaux BJ, Azim E, Arlotta P, Menezes JR, Macklis JD. SOX5 controls the sequential generation of distinct corticofugal neuron subtypes. Neuron. 2008 Jan 24;57(2):232-47.

Molyneaux BJ, Arlotta P, Hirata T, Hibi M, Macklis JD. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron. 2005 Sep 15;47(6):817-31.

Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron. 2005 Jan 20;45(2):207-21.

Callosal Projection Neurons

(Fame, TINS, 2011)

Cederquist GY, Azim E, Shnider SJ, Padmanabhan H, Macklis JD. Lmo4 establishes rostral motor cortex projection neuron subtype diversity. J Neurosci. 2013 Apr 10;33(15):6321-32.

Fame RM, MacDonald JL, Macklis JD. Development, specification, and diversity of callosal projection neurons. Trends Neurosci. 2011 Jan;34(1):41-50.

Molyneaux BJ, Arlotta P, Fame RM, MacDonald JL, MacQuarrie KL, Macklis JD. Novel subtype-specific genes identify distinct subpopulations of callosal projection neurons. J Neurosci. 2009 Sep 30;29(39):12343-54.

Joshi PS, Molyneaux BJ, Feng L, Xie X, Macklis JD, Gan L. Bhlhb5 regulates the postmitotic acquisition of area identities in layers II-V of the developing neocortex. Neuron. 2008 Oct 23;60(2):258-72.

Mitchell BD, Macklis JD. Large-scale maintenance of dual projections by callosal and frontal cortical projection neurons in adult mice. J Comp Neurol. 2005 Jan 31;482(1):17-32.

Neural/Neuronal subtype specification

(Azim, Shnider, et. al. Cereb Cortex, 2009)

Sohur US, Padmanabhan HK, Kotchetkov IS, Menezes JR, Macklis JD. Anatomic and molecular development of corticostriatal projection neurons in mice. Cereb Cortex. 2014 Feb;24(2):293-303.

Cederquist GY, Azim E, Shnider SJ, Padmanabhan H, Macklis JD. Lmo4 establishes rostral motor cortex projection neuron subtype diversity. J Neurosci. 2013 Apr 10;33(15):6321-32.

Sohur US, Arlotta P, Macklis JD. Developmental Controls are Re-Expressed during Induction of Neurogenesis in the Neocortex of Young Adult Mice. Front Neurosci. 2012;6:12.

Jabaudon D, Shnider SJ, Tischfield DJ, Galazo MJ, Macklis JD. RORβ induces barrel-like neuronal clusters in the developing neocortex. Cereb Cortex. 2012 May;22(5):996-1006.

Azim E, Jabaudon D, Fame RM, Macklis JD. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nat Neurosci. 2009 Oct;12(10):1238-47.

Azim E, Shnider SJ, Cederquist GY, Sohur US, Macklis JD. Lmo4 and Clim1 progressively delineate cortical projection neuron subtypes during development. Cereb Cortex. 2009 Jul;19 Suppl 1:i62-9.

Arlotta P, Molyneaux BJ, Jabaudon D, Yoshida Y, Macklis JD. Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J Neurosci. 2008 Jan 16;28(3):622-32.

Emsley JG, Macklis JD. Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol. 2006 Aug;2(3):175-86.

Arlotta P, Macklis JD. Archeo-cell biology: carbon dating is not just for pots and dinosaurs. Cell. 2005 Jul 15;122(1):4-6.

2) Development and Regeneration: applying developmental controls toward brain and spinal cord repair; Autism and related disorders

Relevant reviews:

Sadegh C, Macklis JD. Established monolayer differentiation of mouse embryonic stem cells generates heterogeneous neocortical-like neurons stalled at a stage equivalent to midcorticogenesis. J Comp Neurol. 2014 Aug 15;522(12):2691-706.

Czupryn A, Zhou YD, Chen X, McNay D, Anderson MP, Flier JS, Macklis JD. Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice. Science. 2011 Nov 25;334(6059):1133-7.

Breunig JJ, Arellano JI, Macklis JD, Rakic P. Everything that glitters isn't gold: a critical review of postnatal neural precursor analyses. Cell Stem Cell. 2007 Dec 13;1(6):612-27.

Sohur US, Emsley JG, Mitchell BD, Macklis JD. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells. Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1477-97.

Emsley JG, Mitchell BD, Kempermann G, Macklis JD. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog Neurobiol. 2005 Apr;75(5):321-41.

Emsley JG, Arlotta P, Macklis JD. Star-cross'd neurons: astroglial effects on neural repair in the adult mammalian CNS. Trends Neurosci. 2004 May;27(5):238-40.

Neurogenesis by endogeneous precursors

(Magavi, Nature, 2000)

Emsley JG, Menezes JR, Madeiro Da Costa RF, Martinez AM, Macklis JD. Identification of radial glia-like cells in the adult mouse olfactory bulb. Exp Neurol. 2012 Aug;236(2):283-97.

Macklis JD. Human adult olfactory bulb neurogenesis? Novelty is the best policy. Neuron. 2012 May 24;74(4):595-6.

Sohur US, Arlotta P, Macklis JD. Developmental Controls are Re-Expressed during Induction of Neurogenesis in the Neocortex of Young Adult Mice. Front Neurosci. 2012;6:12.

Fricker-Gates RA, Shin JJ, Tai CC, Catapano LA, Macklis JD. Late-stage immature neocortical neurons reconstruct interhemispheric connections and form synaptic contacts with increased efficiency in adult mouse cortex undergoing targeted neurodegeneration. J Neurosci. 2002 May 15;22(10):4045-56.

Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature. 2000 Jun 22;405(6789):951-5.

Scharff C, Kirn JR, Grossman M, Macklis JD, Nottebohm F. Targeted neuronal death affects neuronal replacement and vocal behavior in adult songbirds. Neuron. 2000 Feb;25(2):481-92.

Integration of transplantated neuronal precursors into complex circuitry

(Czupryn, Science, 2011)

Czupryn A, Zhou YD, Chen X, McNay D, Anderson MP, Flier JS, Macklis JD. Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice. Science. 2011 Nov 25;334(6059):1133-7.

Shin JJ, Fricker-Gates RA, Perez FA, Leavitt BR, Zurakowski D, Macklis JD. Transplanted neuroblasts differentiate appropriately into projection neurons with correct neurotransmitter and receptor phenotype in neocortex undergoing targeted projection neuron degeneration. J Neurosci. 2000 Oct 1;20(19):7404-16.

Extrinsic factors supporting cortical projection neurons

(Ozdinler, Nat Neurosci, 2006)

Tharin S, Kothapalli CR, Ozdinler PH, Pasquina L, Chung S, Varner J, DeValence S, Kamm R, Macklis JD. A microfluidic device to investigate axon targeting by limited numbers of purified cortical projection neuron subtypes. Integr Biol (Camb). 2012 Nov;4(11):1398-405.

Ozdinler PH, Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci. 2006 Nov;9(11):1371-81.

Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3416-21.

Magavi SS, Mitchell BD, Szentirmai O, Carter BS, Macklis JD. Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo. J Neurosci. 2005 Nov 16;25(46):10729-39.

Catapano LA, Arlotta P, Cage TA, Macklis JD. Stage-specific and opposing roles of BDNF, NT-3 and bFGF in differentiation of purified callosal projection neurons toward cellular repair of complex circuitry. Eur J Neurosci. 2004 May;19(9):2421-34.

Catapano LA, Arnold MW, Perez FA, Macklis JD. Specific neurotrophic factors support the survival of cortical projection neurons at distinct stages of development. J Neurosci. 2001 Nov 15;21(22):8863-72.

Directed differentiation of embryonic stem cells to cortical-like neurons

(Sadegh, J Comp Neurol, 2014)

Sadegh C, Macklis JD. Established monolayer differentiation of mouse embryonic stem cells generates heterogeneous neocortical-like neurons stalled at a stage equivalent to midcorticogenesis. J Comp Neurol. 2014 Aug 15;522(12):2691-706.

Degeneration and dysgenesis of neocortical subtypes

Ravits J, Appel S, Baloh RH, Barohn R, Brooks BR, Elman L, Floeter MK, Henderson C, Lomen-Hoerth C, Macklis JD, McCluskey L, Mitsumoto H, Przedborski S, Rothstein J, Trojanowski JQ, van den Berg LH, Ringel S. Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 May;14 Suppl 1:5-18.

Ozdinler PH, Benn S, Yamamoto TH, Güzel M, Brown RH Jr, Macklis JD. Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G⁹³A transgenic ALS mice. J Neurosci. 2011 Mar 16;31(11):4166-77.

Kishi N, Macklis JD. MeCP2 functions largely cell-autonomously, but also non-cell-autonomously, in neuronal maturation and dendritic arborization of cortical pyramidal neurons. Exp Neurol. 2010 Mar;222(1):51-8.

Kishi N, Macklis JD. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci. 2004 Nov;27(3):306-21.

Teaching

SCRB 180

Development and Regeneration in the Mammalian Brain

Catalog Number: 60301
Jeffrey D. Macklis

This course will discuss cellular and molecular mechanisms of regeneration and repair in the mammalian central nervous system (CNS). We will: compare and contrast aspects of neural development with adult neural plasticity; discuss limitations to neuronal regeneration in the mature mammalian CNS following degeneration or injury; examine CNS regeneration approaches directed at overcoming intrinsic limitations; and explore developmental controls and gene manipulation to promote neurogenesis, axonal regeneration, and directed differentiation in the diseased adult brain.
Prerequisite: Life and Physical Sciences A or Life Sciences 1a; Life Sciences 1b; MCB 80 or permission of the instructor.

Freshman Seminar 26K

Transformative Ideas in Brain Science: War, technology, and disease pioneered discovery historically and today

Catalog Number: 93587
Jeffrey D. Macklis

This seminar will offer an integrated historical-neurobiological-neurological introduction to foundational and transformative ideas in the ~3,700 year history of brain science, neuroscience, and “lay” neurology – all accessible to freshmen with interests from history, art, and literature to economics, social policy, and business to neuroscience and (molecular, developmental, organismic, evolutionary, or regenerative) biology. No background will be assumed. Rather, a series of historical vignettes and sources will be tied to modern understanding of elements of the nervous system, its organization, function, and modes of investigation and manipulation– and some historical contexts, often involving war, disease, serendipity, and technology advancement, will be highlighted as advancing knowledge in surprising ways. An inter-disciplinary approach will benefit from each student bringing insights from their own reading of primary source and history of science texts, to be added to in-session discussion, with moderation and direction from me (JDM). We will visit a number of the Harvard Collections and museums, including Comparative Zoology, Herbaria, History of Science, the HMS Warren Anatomical Museum collection (Phineas Gage’s skull and railroad tamping rod), the Harvard collection of historical scientific instruments (advances in microscopy, electrical measurement, e.g.), and the state-of-the-art Center for Brain Science imaging facility, providing context.
Note: open to Freshman only.

SCRB 167

Stem Cells and Regeneration in the Pathobiology and Treatment of Human Disease

Catalog Number: 9556 Enrollment: For advanced students only, seniors and qualified juniors.
George Q. Daley (Medical School) and members of the Department

Stem cells are the basis for tissue maintenance and repair, thus, are essential elements of normal organ and tissue physiology. Stem cells are also targets for disease processes and through transplantation are important therapeutic agents. This course will allow advanced undergraduates to explore how stem cells and tissue regeneration impact human disease pathogenesis and how stem cells might be exploited to advance new therapies for disease.
Prerequisite: Life and Physical Sciences A or Life Sciences 1a; Life Sciences 1b; SCRB 10; MCB 52 or MCB 54.

DRB330qc

Experimental Approaches To Developmental Biology

Catalog Number: 6590

DRB331hc

Critical Analysis & Experimental Approaches In Developmental Biology

Catalog Number: 22543

The DRB “Bootcamp” courses, DRB 331hc and DRB331qc, are designed to provide a survey of major topics and contemporary research in developmental and regenerative biology. Students rotate in the laboratories of DRB faculty across the Harvard campuses and affiliated hospitals. Students engage with faculty and gain hands on experience with a variety of model systems, experimental techniques and research areas. Each day of the course consists of a lecture followed by hands-on laboratory activities and interactive discussions. DRB330qc and DRB331hc will run concurrently.

Neurobiology 304qc

Regeneration and Repair in the Mammalian Nervous System: Cellular and Molecular Mechanisms

Catalog Number: TBA Enrollment: Limited to 18.
Jeffrey D. Macklis, Zhigang He, Larry Benowitz, Clifford Woolf

This course will discuss cellular and molecular approaches and mechanisms to enable regeneration and repair of cellular circuitry in the mammalian nervous system. This will be motivated by prototypical examples in the motor and sensory circuitry connecting the cerebral cortex and spinal cord centrally relevant to spinal cord injury (SCI), ALS / Lou Gehrig’s disease (and related motor neuron disorders), and peripheral nerve injury. We will: compare and contrast aspects of neural development (developmental neurogenesis and axon growth / guidance) with adult neural regeneration and plasticity; discuss limitations to neuronal regeneration in the mature mammalian CNS and PNS following degeneration or injury; examine CNS and PNS regeneration approaches directed at overcoming intrinsic limitations; and explore developmental controls and gene manipulation to promote neurogenesis, directed differentiation, axonal regeneration, and circuit repair in the diseased adult brain. The course will combine overview lectures and critical discussion of central examples from the primary literature.

SCRB 300qc

Current Research in Stem Cell and Regenerative Biology

Catalog Number: 95856
Lee L. Rubin and members of the Department

This survey course provides contemporary approaches to the study of stem cell and regenerative biology. Each week 1-2 SCRB faculty members and graduate students from their labs will introduce a relevant research topic that is of interest to them, emphasizing both new ideas and different types of experimental systems.

Neurobiology 207

Developmental Neurobiology

Catalog Number: 4977
Lisa V. Goodrich (Medical School), Michela Fagiolini (Medical School), Chenghua Gu (Medical School), and Beth Stevens (Medical School)

Advanced topics in nervous system development, including cell fate determination, axon guidance, synapse development and critical periods. Focus on current areas of investigation, unresolved questions, and common experimental approaches.
Prerequisite: Neurobiology 200 or with permission of instructor.

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