Diaz JL, Siththanandan VB, Lu V, Gonzalez-Nava N, Pasquina L, MacDonald JL, Woodworth MB, Ozkan A, Nair R, He Z, Sahni V, Sarnow P, Palmer TD, Macklis JD, Tharin S. An evolutionarily acquired microRNA shapes development of mammalian cortical projections. Proc Natl Acad Sci U S A. 2020 Nov 17; 117(46):29113-29122.

Citation

Diaz JL, Siththanandan VB, Lu V, Gonzalez-Nava N, Pasquina L, MacDonald JL, Woodworth MB, Ozkan A, Nair R, He Z, Sahni V, Sarnow P, Palmer TD, Macklis JD, Tharin S. 2020. An evolutionarily acquired microRNA shapes development of mammalian cortical projections. Proceedings of the National Academy of Sciences of the United States of America. 117(46):29113-29122. Pubmed: 33139574 DOI:10.1073/pnas.2006700117

Abstract

The corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are coexpressed across multiple projection neuron subtypes. Here, we discover 17 CSMN-enriched microRNAs (miRNAs), 15 of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is a demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians' increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.

Related Faculty

Jeffrey Macklis, M.D., D.Sc.Tech.

Macklis Lab

Jeffrey Macklis investigates molecular controls and mechanisms over neuron subtype specification, development, diversity, axon guidance-circuit formation, and pathology in the cerebral cortex. His lab seeks to apply developmental controls toward brain and spinal cord regeneration and directed differentiation for in vitro mechanistic modeling using human assembloids.