SOX5 controls the sequential generation of distinct corticofugal neuron subtypes.
The molecular mechanisms controlling the development of distinct subtypes of neocortical projection neurons, and CNS neuronal diversity more broadly, are only now emerging. We report that the transcription factor SOX5 controls the sequential generation of distinct corticofugal neuron subtypes by preventing premature emergence of normally later-born corticofugal neurons. SOX5 loss-of-function causes striking overlap of the identities of the three principal sequentially born corticofugal neuron subtypes: subplate neurons, corticothalamic neurons, and subcerebral projection neurons. In Sox5(-/-) cortex, subplate neurons aberrantly develop molecular hallmarks and connectivity of subcerebral projection neurons; corticothalamic neurons are imprecisely differentiated, while differentiation of subcerebral projection neurons is accelerated. Gain-of-function analysis reinforces the critical role of SOX5 in controlling the sequential generation of corticofugal neurons--SOX5 overexpression at late stages of corticogenesis causes re-emergence of neurons with corticofugal features. These data indicate that SOX5 controls the timing of critical fate decisions during corticofugal neuron production and thus subtype-specific differentiation and neocortical neuron diversity.
Lai
Tina
T
MGH-HMS Center for Nervous System Repair, Department of Neurosurgery, Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA.
Jabaudon
Denis
D
Molyneaux
Bradley J
BJ
Azim
Eiman
E
Arlotta
Paola
P
Menezes
Joao R L
JR
Macklis
Jeffrey D
JD
D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000166:cytology; D009474:Neurons / Q000145:classification* / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D055755:SOXD Transcription Factors; D013266:Stilbamidines / Q000378:metabolism; D013788:Thalamus / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000502:physiology*
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C511143:Bcl11b protein, mouse; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse; D013266:Stilbamidines; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine