CDX4 regulates the progression of neural maturation in the spinal cord

Abstract The progression of cells down different lineage pathways is a collaborative effort between networks of extracellular signals and intracellular transcription factors. In the vertebrate spinal cord, FGF, Wnt and Retinoic Acidsignaling pathways regulate the progressive caudal-to-rostral maturation of neural progenitors by regulating a poorly understood gene regulatory networkof transcription factors. We have mapped out this gene regulatory networkin the chicken pre- neural tube, identifying CDX4 as a dual-function core component that simultaneously regulates gradual loss of cell potencyand acquisition of differentiation states: in a caudal-to-rostral direction, CDX4 represses the early neural differentiation marker Nkx1.2 and promotes the late neural differentiation marker Pax6. Significantly, CDX4 prevents premature PAX6-dependent neural differentiation by blocking Ngn2 activation. This regulation of CDX4 over Pax6is restricted to the rostral pre- neural tubeby Retinoic Acidsignaling. Together, our results show that in the spinal cord, CDX4 is part of the gene regulatory networkcontrolling the sequential and progressive transitionof statesfrom high to low potency during neural progenitor maturation. Given CDX well-known involvement in Hox generegulation, we propose that CDX factors coordinate the maturation and axial specification of neural progenitor cells during spinal cord development.