Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord

Abstract

The development of animal embryos depends on accurate coordination of the growth and specification of precursor cells. Morphogens, extracellular signals that act at a distance to control cell fate, are crucial in the patterning of embryonic tissues. One of the most extensively studied examples of a morphogen patterned tissue is the developing vertebrate spinal cord. The distribution of distinct neuronal subtypes along the dorsoventral (DV) axis of the spinal cord is determined by counteracting gradients of long-range signals. Wnt and BMP signals promote dorsal identities, while Shh signaling induces ventral identities. Simultaneous to their specification, neural progenitors proliferate, facilitating the growth of the neural tube. In this review we discuss evidence indicating that the signals governing progenitor specification also control proliferation and survival of progenitor cells. Moreover, evidence of reciprocal transcriptional interactions and cross-talk between the signaling pathways has emerged from recent studies. Together these studies suggest ways in which patterning and growth may be coordinated in the spinal cord. One level of interaction is an inhibitory regulation of repressor forms of the transcription factor Gli3-generated in the absence of Shh-on b-catenin activity, the transcription factor activated by Wnt signaling. This interaction may also be relevant in other tissues and situations in which the two signaling pathways are known to participate.

Sonic Hedgehog Regulates Integrin Activity, Cadherin Contacts, and Cell Polarity to Orchestrate Neural Tube Morphogenesis

“…During neural tube morphogenesis, HH signaling pathway simultaneously controls progenitor specification and proliferation (Ulloa and Briscoe, 2007). Here, we show that Shh is also able to coordinate cell adhesion and polarity during neural tube formation by controlling integrin-matrix adhesion, cell-cell cadherin contacts, and cell polarity genes.…”

Stage- and area-specific control of stem cells in the developing nervous system

“…Neuronal subtype specification within the CNS begins with the molecular regionalization of the neuroepithelium. This involves a three dimensional patterning process imposed by morphogens gradients with distinct spatial orientation and signaling ranges [2] ( Figure 1). Patterning along the anterior posterior axis depends, among others, on rostrocaudal gradients of FGF's and Retinoic acid (RA) that induce different Hox expression profiles.…”

“…Regionalization of the neural tube along the dorso-ventral axis depends on signaling centers localized at the midline, namely the notochord and floor plate ventrally and the roof plate dorsally. The notochord and the floor plate secret the morphogen Sonic hedgehog (Shh) that induces ventral identities [5,6], while the roof plate produces a counteracting gradient of Wnt and BMP signals promoting dorsal identities [2,[7][8][9]. Given the regional specification of the developing nervous system the question arises of how NSCs in different areas and at different time points are regulated with respect to proliferation, fate decision, and differentiation.…”

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

“…A small number of conserved signaling pathways act via secreted ligands to establish these embryonic patterns, producing distinct cellular responses in a concentration-and time-dependent manner (Freeman, 2000;Kutejova et al, 2009;Ulloa and Briscoe, 2007). These pathways require precise spatial and temporal control of ligand production and distribution to preserve the requisite diversity of cellular responses and to limit signaling within the appropriate domains.…”