TY - JOUR
T1 - An evolutionarily acquired microRNA shapes development of mammalian cortical projections
AU - Diaz, Jessica L.
AU - Siththanandan, Verl B.
AU - Lu, Victoria
AU - Gonzalez-Nava, Nicole
AU - Pasquina, Lincoln
AU - MacDonald, Jessica L.
AU - Woodworth, Mollie B.
AU - Ozkan, Abdulkadir
AU - Nair, Ramesh
AU - He, Zihuai
AU - Sahni, Vibhu
AU - Sarnow, Peter
AU - Palmer, Theo D.
AU - Macklis, Jeffrey D.
AU - Tharin, Suzanne
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Laure Aurelian for scientific discussions and for critically reading the manuscript. We thank members of the J.D.M., T.D.P., P.S., and S.T. laboratories for scientific discussions and helpful suggestions. This work was supported by grants from the NIH (K08 NS091531), AOSpine North America (Young Investigator Research Grant Award), a Stanford McCormick Faculty Award, and a Stanford Maternal and Child Health Research Institute Pilot Award (to S.T.). S.T. is a Tashia and John Morgridge Endowed Faculty Scholar in Pediatric Translational Medicine of
Funding Information:
the Stanford Maternal and Child Health Research Institute. This work was also supported by grants from the NIH (R01s NS045523 and NS075672, with additional infrastructure supported by NS041590, NS049553, and DP1 NS106665), the ALS Association, and the Travis Roy Foundation to J.D.M., by a grant from the NIH (R01 AI069000) to P.S., and by grants from the NIH (1R01MH108660-01, 1R01MH108659-01, and R21NS096447) (to T.D.P.). J.L.D. was supported by the comparative medicine biosciences training program (5T32OD011121-12). We acknowledge the Stanford Neuroscience Microscopy Service, supported by NIH NS069375. We gratefully acknowledge Michelle Monje for access to the electroporator and Paul Buckmaster for use of the sliding microtome.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/11/17
Y1 - 2020/11/17
N2 - 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.
AB - 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.
KW - Cerebral cortex | cortical development | microRNA | motor neuron | projection neuron
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U2 - 10.1073/pnas.2006700117
DO - 10.1073/pnas.2006700117
M3 - Article
C2 - 33139574
AN - SCOPUS:85096361686
SN - 0027-8424
VL - 117
SP - 29113
EP - 29122
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -