Resumen de Role of the tgf-betaintracellular effectors in neuronal differentiation in the developing spinal cord - papel de los efectores de la vía de señalización tgf-beta en la diferenciación neuronal en la médula espinal en desarrollo
BMPs are proposed to act in a concentration dependent manner to regulate differentiation of neural crest, roof plate and dorsal horn neurons during spinal cord development, although demonstration of a BMP gradient has been elusive. Using an engineered reporter we show here that equal levels of BMP activity generate different cellular responses along neural tube development, arguing against a morphogen-like signal. Instead we provide evidence that it is the choice of a particular Smad effector what regulates specific gene responses. In vivo gain-of-function experiments indicate that different BMP-Smads regulate specific gene responses. Generation of neural crest progenitors might require the combined activity of Smad1 and Smad5 at the appropriate time and location to induce the expression of an array of neural crest cell markers, including Sox9, Slug/Snail2 and FoxD3. This capacity is lost over time and instead same effectors of the BMP pathway acquire novel activities controlling the generation of dorsal horn neurons. Thus, Smad1 controls the generation of dl1-2 neurons, while Smad5 controls the differentiation of dl2-3 neurons. These activities, however, appear to be dependent on the levels of activity of individual R-Smad proteins. These data support a model in which a temporal code of Smad activity operates to direct specific BMP responses. Moreover, TGFß signalling through Smad3 seems to counteract BMP activity in the dorsal spinal cord and induces the generation of dl4/6 at the expense of dl1-3 neurons.
We also show here that Smad3, an effector of TGFß/Activin signalling, is expressed in unique progenitor domains along the dorsoventral axis of the developing chick spinal cord. Restriction of Smad3 expression to the pMN/p2 and pMN/p3 domain boundaries together with its exclusion from pMN domain progenitors, results from the cross-repressive activity of class II HD and bHLH transcription factors involved in patterning the neural tube. Smad3-mediated TGFß signalling promotes neurogenesis progression through its ability to repress Id gene expression, and thus enabling the neurogenic activity of proneural bHLH proteins. Furthermore, in the context of pMN domain progenitors, ectopic Smad3 activity suppresses the generation of motor neurons that results in ectopic generation of ventral interneurons. We conclude that the absence of Smad3 expression in the pMN domain during pattern formation at early developmental stages is crucial for the generation of motor neurons.
