Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord

Abstract

In the developing spinal cord, signals from the roof plate are required for the development of three classes of dorsal interneuron: D1, D2, and D3, listed from dorsal to ventral. Here, we demonstrate that absence of Wnt1 and Wnt3a, normally expressed in the roof plate, leads to diminished development of D1 and D2 neurons and a compensatory increase in D3 neuron populations. This occurs without significantly altered expression of BMP and related genes in the roof plate. Moreover, Wnt3a protein induces expression of D1 and D2 markers in the isolated medial region of the chick neural plate, and Noggin does not interfere with this induction. Thus, Wnt signaling plays a critical role in the specification of cell types for dorsal interneurons. Received August 13, 2001; revised version accepted January 10, 2002. During development of the vertebrate central nervous system (CNS), highly proliferative cells in the ventricular zone of the neural tube serve as progenitors of the various types of neurons, such as interneurons and motor neurons. In the ventral half of the spinal cord, the secreted signaling molecule Sonic hedgehog (Shh) functions as a gradient signal for the generation of five distinct classes of neurons along the dorsoventral axis. Shh secreted from the notochord and floor plate controls the specification of ventral cell types in a dose-dependent manner Ericson et al. 1996;Tanabe and Jessell 1996;Jessell 2000).Three subclasses of interneuron, called D1, D2, and D3 positioned from the dorsal side, are indicated by the expression of homeodomain proteins LH2, Islet1, and Lim1/2 in the dorsal half of the spinal cord (Liem et al. 1997). These dorsal interneurons are derived from progenitors in the ventricular zone. These progenitors are also subdivided by expression of the basic helix-loophelix (bHLH) proteins Math1, Neurogenin1 (Ngn1), and Mash1 (Lee et al. 1998(Lee et al. , 2000. It has been established that Math1-expressing cells give rise to LH2 + neurons (Helms and Johnson 1998). Recent studies indicate that the roof plate is the major source of inductive signals controlling the generation of the D1 and D2 classes of dorsal interneuron (Lee and Jessell 1999). Experiments using cultured chick neural plate tissue have demonstrated that signals from the roof plate are sufficient to promote dorsal interneuron differentiation in vitro (Liem et al. 1997). Moreover, absence of D1/D2 class neurons in mouse embryos lacking the roof plate, either by homozygosity of the dreher (dr) allele carrying a loss-of-function mutation in the LIM-homeobox gene Lmx1, or by genetic roof plate ablation, has provided compelling evidence for the roof plate as the determinant source of dorsal interneurons (Lee et al. 2000;Millonig et al. 2000).Around the time when dorsal interneurons are generated, cells at the dorsal end of the neural tube express secretory proteins belonging to BMP, FGF, and Wnt families (Lee and Jessell 1999). It has been shown in the chick that BMP family proteins mimic the roof plate in the induction of dorsal...

Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube

“…These data suggest that the Shh and BMP signalling pathways intersect and that BMPs act to limit the ventralizing activity of Shh. In addition to BMPs, Wnt proteins emanating from the dorsal midline have also been found to affect neural progenitor behaviour and neuronal identity (Muroyama et al 2002). Wnt signals appear to promote progenitor proliferation throughout the neural tube (Megason & McMahon 2002;Chesnutt et al 2004), and have also been suggested to inhibit Shh signalling and, consequently, the generation of ventral cell types (Robertson et al 2004).…”

The basic helix–loop–helix olig3 establishes the neural plate boundary of the trunk and is necessary for development of the dorsal spinal cord

“…The expression of olig3 in the lateral domain of the neuroectoderm at the shield stage suggests that early genetic events restrict its expression ventrally. Because Wnt signaling is required for polarization of the early vertebrate embryo and the specification of the dorsal neuroectoderm (29,30), olig3 might be implicated in the regulation of neural plate and neural crest fates under the control of the blastula Wnt gradient. To test this hypothesis, we analyzed the olig3 expression pattern in embryos in which the Wnt signaling is increased or impaired.…”

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

“…Ventrally, Sonic hedgehog (SHH) drives the position and identity of ventral neurons (Briscoe and Novitch, 2008). In addition to BMPs, Wnt proteins also regulate dorsal progenitor proliferation and identity (Muroyama et al, 2002). Recently, evidence have been obtained showing that SHH also influences NE cell proliferation and survival (Cayuso et al, 2006), suggesting that gradients emanating from opposite poles in the neural tube, BMPs/Wnts dorsally and SHH ventrally, simultaneously control neural growth and patterning.…”