Inhibitory Smads differentially regulate cell fate specification and axon dynamics in the dorsal spinal cord

Abstract

The roof plate resident BMPs have sequential functions in the developing spinal cord, establishing cell fate and orienting axonal trajectories. These activities are, however, restricted to the dI1–dI3 neurons in the most dorsal region of the spinal cord. What limits the extent of the action of the BMPs to these neurons? To address this question, we have examined both the distribution of the inhibitory Smads (I-Smads), Smad6 and Smad7 in the spinal cord and the consequence of ectopically expressing the I-Smads in chicken embryos. Our studies suggest that the I-Smads function in vivo to restrict the action of BMP signaling in the dorsal spinal cord. Moreover, the I-Smads have distinct roles in regulating the diverse activities of the BMPs. Thus, the ectopic expression of Smad7 suppresses the dI1 and dI3 neural fates and concomitantly increases the number of dI4–dI6 spinal neurons. In contrast, Smad6 most potently functions to block dI1 axon outgrowth. Taken together, these experiments suggest that the I-Smads have distinct roles in spatially limiting the response of cells to BMP signaling.

Type Ib BMP receptors mediate the rate of commissural axon extension through inhibition of cofilin activity

“…Our studies (Phan et al, 2010;Hazen et al, 2011;Hazen et al, 2012) have lent support to a model in which these activities are differentially translated at both the receptor and second messenger levels. In this model, a shared activity of type I Bmprs is to mediate the specification of the dorsal-most cell fates by activating the BMP receptor-regulated Smads (Hazen et al, 2012), the canonical second messenger intermediates (Heldin et al, 1997).…”

“…Limk1 is only present in post-mitotic spinal neurons (Phan et al, 2010). The direct interaction of Limk1 with BmprII (Foletta et al, 2003;Lee-Hoeflich et al, 2004) followed by BMP dimerization of the Bmpr complex might result in a downstream response that either bypasses or works in conjunction with the canonical Smad signaling pathway (Hazen et al, 2011;Hazen et al, 2012).…”

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

“…However, some molecules, such as Ephs and netrin1, have been identified as regulators of nigrostriatal pathway development in recent years (Hegarty et al 2013a; Van den Heuvel and Pasterkamp 2008). In an attempt to identify new candidate molecules and signalling pathways that may be involved in nigrostriatal development, this study focused on two BMPs, GDF5 and BMP2, since both of these factors have been implicated in axonal growth in (Parikh et al 2011;Hazen et al 2011Hazen et al , 2012Phan et al 2010;Niere et al 2006;Lein et al 1995;Hegarty et al 2013a) and have been shown to have neurotrophic effects on VM DA neurons, specifically survivaland neurite growth-promoting effects (O'Keeffe et al 2004a;Reiriz et al 1999;Jordan et al 1997;Sullivan et al 1997;Hegarty et al 2014). Despite these studies, the downstream molecular mechanisms that mediate the effects of GDF5 and BMP2 on VM DA neurons are unknown.…”

“…The two members of the BMP family of proteins, BMP2 and a related molecule GDF5, have been shown to regulate neurite growth in the dorsal SC (Parikh et al 2011;Hazen et al 2011Hazen et al , 2012Phan et al 2010;Niere et al 2006). GDF5 and BMP2 both activate a canonical signalling pathway involving two types of serine/threonine kinase receptors, type I and type II BMPRs (ten Dijke et al 1994;Koenig et al 1994;Yamashita et al 1996;Shi and Massague 2003).…”

Canonical BMP7 activity is required for the generation of discrete neuronal populations in the dorsal spinal cord

“…On the one hand, Xie and colleagues (Xie et al, 2011) found that, in the dorsal spinal cord, Smad6 promotes neuronal differentiation by repressing the Wnt canonical pathway, and thus resulting in the reduced proliferation rate of neural progenitors. On the other hand, Hazen and colleagues (Hazen et al, 2011) showed that electroporation of Smad6 or Smad7, at the time of dIN neurogenesis, results in a reduction of dI1 and dI3, without the compensatory increase of dI4 neurons. These data strongly support our findings, as well as the requirement for a finely tuned regulation of BMP activity during primary neurogenesis.…”