An evolutionarily acquired microRNA shapes development of mammalian cortical projections

Jessica L. Diaz, Verl B. Siththanandan, Victoria Lu, Nicole Gonzalez-Nava, Lincoln Pasquina, Jessica L. MacDonald, Mollie B. Woodworth, Abdulkadir Ozkan, Ramesh Nair, Zihuai He, Vibhu Sahni, Peter Sarnow, Theo D. Palmer, Jeffrey D. Macklis, Suzanne Tharin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)29113-29122
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020
Externally publishedYes

Keywords

  • Cerebral cortex | cortical development | microRNA | motor neuron | projection neuron

ASJC Scopus subject areas

  • General

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