The role of Sox4 and Sox11 in cortical development
The formation of a central nervous system, including the cerebral cortex, requires specialized molecular cascades to direct the expansion of progenitor pools, the differentiation of cells, and the maturation of discrete neuronal subtypes, together ensuring that the correct amounts and classes of neurons are generated. In several neural systems, the SoxC transcription factors, particularly Sox11 and Sox4, have been characterized as functioning exclusively and redundantly in promoting neuronal differentiation. The precise role of SoxC in cortical neuronal differentiation during development, however, is not well characterized. In examining Sox11 and Sox4 in the formation of mouse cerebral cortex, distinct expression patterns and mutant phenotypes revealed that Sox11 and Sox4 are not redundant, but rather act in overlapping and discrete populations of neurons. Sox11 acts in early born neurons: binding to its partner protein, Neurogenin1, leading to selective targeting and transactivation of a downstream gene, NeuroD1. In addition to its neuronal expression, Sox4 was unexpectedly expressed in intermediate progenitor cells, the transit amplifying cell of the cerebral cortex. Sox4 mutant analyses reveal a requirement for Sox4 in IPC specification and maintenance. In IPCs, Sox4 partners with the proneural gene Neurogenin2 to activate Tbrain2 and then with Tbrain2 to maintain this cell fate. Together, this work reveals an intricately structured molecular architecture for SoxC proteins, with Sox11 acting in a select set of cortical neurons and Sox4 playing an hitherto unknown role in designating secondary progenitors.We also addressed the role of Sox11 from an evolutionary perspective by examining the expression and function of Sox11 in the cerebral cortex of mouse compared to the nervous system of frog. Limited expression of Sox11 in neural tissue is conserved between these species. Additionally, functional studies of Sox11 demonstrate similar roles in promoting neuronal differentiation.Finally, regulatory strategies responsible for the initial activation of Sox4 were examined. A microRNA was implicated: knockdown of mature microRNA-92a promoted Sox4+, Tbr2+ positive intermediate progenitor cells. These results demonstrate an important role for miRNAs in regulating Sox4 activation in the developing mouse cerebral cortex.In conclusion, discrete cells and functions are subserved by the actions of either Sox11 or Sox4.
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