Regulation of the neural patterning activity of sonic hedgehog by secretedBMP inhibitors expressed by notochord and somites

The secretion of Sonic hedgehog (Shh) from the notochord and floor plate ap pears to generate a ventral-to-dorsal gradient of Shh activity that directs progenitor cell identity and neuronal fate in the ventral neural tube, In principle, the establishment of this Shh activity gradient could be achieve d through the graded distribution of the Shh protein itself, or could depen d on additional cell surface or secreted proteins that modify the response of neural cells to Shh, Cells of the neural plate differentiate from a regi on of the ectoderm that has recently expressed high levels of BMPs, raising the possibility that prospective ventral mural cells are exposed to residu al levels of BMP activity. We have examined whether modulation of the level of BMP signaling regulates neural cell responses to Shh, and thus might co ntribute to the patterning of cell types in the ventral neural tube. Using an in vitro assay of neural cell differentiation we show that BMP signaling markedly alters neural cell responses to Shh signals, eliciting a ventral- to-dorsal switch in progenitor cell identity and neuronal fate. BMP signali ng is regulated by secreted inhibitory factors, including noggin and follis tatin, both of which are expressed in or adjacent to the neural plate, Conv ersely, follistatin but not noggin produces a dorsal-to-ventral switch in p rogenitor cell identity and neuronal fate in response to Shh both in vitro and in vivo. These results suggest that the specification of ventral neural cell types depends on the integration of Shh and BMP signaling activities. The net level of BMP signaling within neural tissue may be regulated by fo llistatin and perhaps other BMP inhibitors secreted by mesodermal cell type s that flank the ventral neural tube.