IMCB congratulates Ashish Maurya on receiving the EMBO best poster prize
IMCB congratulates Ashish Maurya on receiving the best poster prize at the EMBO workshop titled "HEDGEHOG SIGNALING: From developmental biology to anti-cancer drugs" in Saint Jean Cap Ferrat, France. Ashish is currently a Ph.D. student in Prof. Philip Ingham’s laboratory.
Shh antagonizes Smad activity to specify cell fates in the teleost myotome "HEDGEHOG SIGNALING: Ashish K Maurya1,2, Marcel Souren1,3, Joachim Wittbrodt3 & Philip W Ingham1,2
1 - Institute of Molecular and Cell Biology, Singapore;
2 - Dept of Biological Sciences, National University of Singapore;
3 - EMBL Heidelberg
The zebrafish myotome consists of four identifiable muscle cell types, three of which require Hedgehog (Hh) signaling activity for their specification.
We are trying to understand how the same Hh signal can elicit distinct cellular identities using the myotome as a paradigm. We have focussed on the two cell types that require the highest levels of Hh for their specification, Muscle Pioneers (MPs) and Medial Fast Fibers (MFFs). Both of these muscle cell types express engrailed genes in response to Hh signaling. In order to understand the specification of these cell types, we have analysed the transcriptional control of the engrailed genes. We started by identifying a minimal cis-regulatory element from the engrailed2a (en2a) locus that can drive reporter gene expression in the MPs and MFFs. We next took a cell culture based approach to identify potential trans-acting factors regulating this element and identified Smad5 - a mediator of BMP signaling - as a strong repressor of this element. We next visualized activated Smads (using a specific antibody phospho-Smad1/5/8) in the zebrafish myotome and found that many myoblasts accumulate pSmads in their nuclei, whereas Engrailed positive fibers are devoid of such accumulation, consistent with Smads acting as repressors of engrailed. We next altered cell fates in the myotome by manipulating levels of Hh signaling and assayed for the distribution of activated Smads. As previously described, elevated Hh signaling resulted in an increase in the number of MP/MFFs, and we found a concomitant depletion of activated Smads from these ectopic engrailed positive cells. We next manipulated BMP signaling cell autonomously in the myotome using a constitutively active BMP receptor or by inhibitory Smads, Smad6 and 7. Activating BMP signaling led to a suppression of MP/MFF fate, whereas removal of activated Smads resulted in ectopic MP/MFF fate within the myotome. These experiments suggest that Hh specifies MP/MFF cell fate by antagonizing BMP signaling.
This antagonistic interaction parallels the interplay between BMP and Hh activity underlying cell fate specifciation in the vertebrate neural tube. Based on previously reported interaction between Smads and repressor forms of Glis (trans-factors that mediate Hh signals) we suggest a model whereby activated Smads are stabilized and restrained in the nucleus by repressive forms of Glis, resulting in suppression of the MP/MFF fate.