Función de Sox5 en la regionalización del tubo neural de vertebrados

Resumen

During the development of the central nervous system, a large number of different neurons and glial cells are generated form a small population of self renewing cells. In the neural tube progenitors are located in the medial ventricular zone and they migrate laterally to the mantle zone upon exiting the cell cycle, a site where differentiating, post-mitotic cells accumulate. Distinct neuronal subtypes emerge from progenitor cells in a precise spatial order, partitioning the dorsoventral axis of the neural tube into discrete regions that are occupied by different neural precursors and neuronal subtypes. The correct coordination of these events requires high spatio-temporal control. The HMG-box transcription factors of the Sox gene family could be at the core of those processes, as they have regulatory functions during neurogenesis in the vertebrate central nervous system. In fact, previous studies in the laboratory have established that Sox5 controls the timing of cell cycle exit of neural precursors at the G1/S transition, by counteracting the mitotic effect of the Wnt/ß-catenin pathway. In the dorsal neural tube Wnt canonical pathway, acting through the Tcf/ß-catenin transcription complex, also controls the specification of dorsal progenitors and interneurons. In this study we have described that in chick embryos Sox5 is expressed dynamically in spatially restricted neural precursors in the spinal cord. Furthermore, Sox5 is expressed in a very similar pattern in mouse and medaka fish embryos. Using gain and loss of function analysis, we have determined that Sox5 controls cell fate specification of dorsal neural progenitors inducing the transcription of the negative Wnt pathway regulator Axin2. We have established that Sox5 promotes Axin2 transcription together with Tcf/ß-catenin through direct binding to a conserved binding site present in Aixn2 first intron. By that way, Sox5 could limit the extent of dorsal identity imposed by Wnt signaling in the central nervous system. In conclusion, Sox5 coordinates proliferation and dorsal patterning during the development of the spinal cord.