Neuronal subtype diversification is essential for the establishment of functional neural circuits, and yet the molecular events underlying neuronal diversity remain largely to be defined. During spinal neurogenesis, the p2 progenitor domain, unlike others in the ventral spinal cord, gives rise to two intermingled but molecularly distinct subtypes of interneurons, termed V2a and V2b. We show here that the Foxn4 winged helix͞forkhead transcription factor is coexpressed with the bHLH factor Mash1 in a subset of p2 progenitors. Loss of Foxn4 function eliminates Mash1 expression and V2b neurons and causes a fate-switch to V2a neurons, whereas the absence of Mash1 displays a similar but less severe phenotype. Overexpression of Foxn4 alone in spinal neural progenitors promotes the V2a fate at the expense of the V2b fate, whereas Mash1 suppresses both the V2a and V2b fates. However, coexpression of both Foxn4 and Mash1 promotes the V2b fate while inhibiting the V2a fate, indicating that Foxn4 cooperates with Mash1 to specify the identity of V2b neurons from bipotential p2 progenitors.winged-helix͞forkhead ͉ transcription factor ͉ p2 progenitor ͉ spinal neurogenesis
Shh-Gli signaling controls cell fates in the developing ventral neural tube by regulating the patterned expression of transcription factors in neural progenitors. However, the molecular mechanisms that limit target gene responses to specific domains are unclear. Here, we show that Wnt pathway inhibitors regulate the threshold response of a ventral Shh target gene, Nkx2.2, to establish its restricted expression in the ventral spinal cord. Identification and characterization of an Nkx2.2 enhancer reveals that expression is directly regulated by positive Shh-Gli signaling and negative Tcf repressor activity. Our data indicate that the dorsal limit of Nkx2.2 is controlled by Tcf4-mediated transcriptional repression, and not by a direct requirement for high-level Shh-Gli signaling, arguing against a simple model based on differential Gli factor affinities in target genes. These results identify a transcriptional mechanism that integrates graded Shh and Wnt signaling to define progenitor gene expression domains and cell fates in the neural tube.
Proper central nervous system (CNS) function depends critically on the generation of functionally distinct neuronal types in specific and reproducible positions. The generation of neuronal diversity during CNS development involves a fine balance between dividing neural progenitors and the differentiated neuronal progeny that they produce. However, the molecular mechanisms that regulate these processes are still poorly understood. Here, we show that the Prox1 transcription factor, which is expressed transiently and specifically in spinal interneurons, plays an important role in neurogenesis. Using both gain-and loss-offunction approaches, we find that Prox1 is capable of driving neuronal precursors out of the cell cycle and can initiate limited expression of neuronal proteins. Using RNAi approaches, we show that Prox1 function is required to execute a neurogenic differentiation program downstream of Mash1 and Ngn2. Our studies demonstrate an important, spinal interneuron-specific role for Prox1 in controlling steps required for both cell-cycle withdrawal and differentiation. Developmental Dynamics 237:393-402, 2008.
Both the BMP and Wnt pathways have been implicated in directing aspects of dorsal neural tube closure and cell fate specification. However, the mechanisms that control the diverse responses to these signals are poorly understood. In this study, we provide genetic and functional evidence that the secreted sFRP1 and sFRP2 proteins, which have been primarily implicated as negative regulators of Wnt signaling, can also antagonize BMP signaling in the caudal neural tube and that this function is critical to maintain proper neural tube closure and dorsal cell fate segregation. Our studies thus reveal a novel role for specific sFRP proteins in balancing the response of cells to two critical extracellular signaling pathways.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.