ZFIN ID: ZDB-PUB-130710-38
Cited3 activates Mef2c to control muscle cell differentiation and survival
Devakanmalai, G.S., Zumrut, H.E., and Ozbudak, E.M.
Vertebrate muscle development occurs through sequential differentiation of cells residing in somitic mesoderm – a process
that is largely governed by transcriptional regulators. Our recent spatiotemporal microarray study in zebrafish has identified
functionally uncharacterized transcriptional regulators that are expressed at the initial stages of myogenesis. cited3 is one such novel gene encoding a transcriptional coactivator, which is expressed in the precursors of oxidative slow-twitch
myofibers. Our experiments placed cited3 into a gene regulatory network, where it acts downstream of Hedgehog signaling and myoD/myf5 but upstream of mef2c. Knockdown of expression of cited3 by antisense morpholino oligonucleotides impaired muscle cell differentiation and growth, caused muscle cell death and eventually
led to total immotility. Transplantation experiments demonstrated that Cited3 cell-autonomously activates the expression of
mef2c in slow myofibers, while it non-cell-autonomously regulates expression of structural genes in fast myofibers. Restoring expression
of cited3 or mef2c rescued all the cited3 loss-of-function phenotypes. Protein truncation experiments revealed the functional necessity of C-terminally conserved domain
of Cited3, which is known to mediate interactions of Cited-family proteins with histone acetylases. Our findings demonstrate
that Cited3 is a critical transcriptional coactivator functioning during muscle differentiation and its absence leads to defects
in terminal differentiation and survival of muscle cells.