The Activin signaling pathway promotes differentiation of dI3 interneurons in the spinal neural tube

Abstract

The generation of the appropriate types and numbers of mature neurons during the development of the spinal cord requires the careful coordination of patterning, proliferation, and differentiation. In the dorsal neural tube, this coordination is achieved by the combined action of multiple ligands of both the Wnt and TGF-beta families, and their effectors, such as the bHLH proteins. TGF-beta signaling acting through the BMP receptors is necessary for the generation of several dorsal interneuron types. Other TGF-beta ligands expressed in the dorsal neural tube interact with the Activin receptors, which signal via a different set of SMAD proteins than BMPs. The effects of Activin signaling on the developing neural tube have not been described. Here we have activated the Activin signal transduction pathway in a cell-autonomous manner in the developing chick neural tube. We find that a constitutively active Activin receptor promotes differentiation throughout the neural tube. Although most differentiated cell populations are unaffected by Activin signaling, the number of dorsal interneuron 3 (dI3) cells is specifically increased. Our data suggest that Activin signaling may promote the formation of the dI3 precursor cells within a region circumscribed by BMP signaling and that this function is not dependent upon BMP signaling.

The TGFβ intracellular effector Smad3 regulates neuronal differentiation and cell fate specification in the developing spinal cord

“…In the developing spinal cord, our results show that Smad3 overexpression upregulated the cyclin-dependent kinase inhibitor p27 kip1 , resulting in cell-cycle exit and further contributing to neuronal differentiation. Induction of neuronal differentiation by activin signaling has also been reported in the developing spinal cord (Timmer et al, 2005), and our results suggest that this activity is mediated by Smad3. In addition, loss of endogenous Smad3 by in ovo RNA interference resulted in reduced expression of p27 kip1 , thereby supporting a model in which Smad3 activity regulates p27 kip1 expression in the developing spinal cord and contributes to neurogenesis.…”

Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors

“…By inhibiting the pathway that controls self-renewal and enhancing the response to the pro-neurogenic pathway, Activin ensures that the whole differentiation process of telencephalic neural progenitors is tightly regulated. The fact that in neural precursors derived from hESCs (our work) and in the chick spinal cord 41,42 Activin also promotes differentiation suggests that this role may be conserved in a wide variety of neuronal settings. Interestingly, in the chick neural tube the Activin effector Smad3 induces differentiation by activating p27 kip1 expression 42 .…”

The Onecut Transcription Factors Regulate Differentiation and Distribution of Dorsal Interneurons during Spinal Cord Development

“…The fraction of dorsal populations containing OC proteins increases from dI2 to dI6 and the number of cells that maintain Oc expression at e12.5 also rises from dI2 to dI6 (Figures 1–3). This is reminiscent of the gradient of Wnt and BMP morphogens initially produced by the dorsal ectoderm and subsequently maintained by the roof plate, which determines the identity of the three dorsal-most progenitor compartments without affecting the more ventral populations (Wine-Lee et al, 2004; Timmer et al, 2005; Zechner et al, 2007; Tozer et al, 2013). While expression of receptor Ia to BMP (BMPRIa) is restricted to spinal progenitors, BMPRIb is additionally expressed in the intermediate zone and in differentiating neurons (Yamauchi et al, 2008).…”

“…Dorso-ventral (DV) gradients of BMP and Wnt signaling contribute to specify three dorsal progenitor domains (pdI1–3) according to their position along the DV axis (Wine-Lee et al, 2004; Timmer et al, 2005; Zechner et al, 2007; Tozer et al, 2013), whereas generation of the three more ventral domains (pdI4–6) occurs independently of these signals (Zhuang and Sockanathan, 2006; Le Dréau and Martí, 2012; Lai et al, 2016). Specific combinations of pro-neural factors and of bHLH or homeodomain proteins direct the identity of the post-mitotic neuronal populations generated from these domains (Zhuang and Sockanathan, 2006; Lai et al, 2016).…”