A network of genetic repression and derepression specifies projection fates in the developing neocortex

作者：Srinivasan Karpagam; Leone Dino P; Bateson Rosalie K; Dobreva Gergana; Kohwi Yoshinori; Kohwi Shigematsu Terumi; Grosschedl Rudolf; McConnell Susan K^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(47): 19071-19078.

DOI：10.1073/pnas.1216793109

• cell fate
• cerebral cortex
• axon guidance
• transcription factor

Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes-Fezf2, Ctip2, Tbr1, and Satb2-regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2, and Satb2, that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that Tbr1, EphA4, and Unc5H3 are critical downstream targets of Satb2 in callosal fate specification. This represents a unique role for Tbr1, implicated previously in specifying corticothalamic projections. We further show that Tbr1 expression is dually regulated by Satb2 and Ctip2 in layers 2-5. Finally, we show that Satb2 and Fezf2 regulate two disease-related genes, Auts2 (Autistic Susceptibility Gene2) and Bhlhb5 (mutated in Hereditary Spastic Paraplegia), providing a molecular handle to investigate circuit disorders in neurodevelopmental diseases.

• 出版日期2012-11-20