Receptor tyrosine kinase signaling is critical for mammalian craniofacial development but

Receptor tyrosine kinase signaling is critical for mammalian craniofacial development but the key downstream transcriptional effectors remain unknown. migration during craniofacial development and delineate a mechanism of receptor tyrosine kinase specificity mediated through differential cofactor usage leading to a unique PDGF-responsive SRF-driven transcriptional program in OSI-930 the midface. phenotypes associated with different RTK mutants can be quite unique (Lemmon and Schlessinger OSI-930 2010). A central question revolves around how transmission specificity arises from a seemingly general set of transduction pathways. At a transcriptional level RTK signaling classically modulates the expression of immediate early genes (IEGs) (Cochran et al. 1984; Lau and Nathans 1987). While different RTK pathways such as platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling induce comparable units of IEGs in cultured cells (Fambrough et al. 1999) genetic experiments in mice suggest a degree OSI-930 of IEG specificity downstream of PDGF signaling (Schmahl et al. 2007). Thus a major goal remains to characterize the key transcriptional mediators regulated by RTK signaling and determine their specificity downstream of different receptors. Development of the mammalian face comprises derivatives from all three germ layers including a unique contribution from your neural crest. Many components of RTK signaling are linked to craniofacial syndromes and phenotypes in both mice and humans (Newbern et al. 2008; Bentires-Alj et al. 2006). Mice harboring neural crest cell (NCC) conditional loss of PDGF receptor �� (PDGFR��) using the transgene exhibit cleft face and palate (Tallquist and Soriano 2003). Combined loss of both PDGFR��-specific ligands PDGFA and PDGFC results in facial clefting (Ding et al. 2004). In humans mutations in and around PDGFC (Choi et al. 2009; Calcia et al 2013) and PDGFR�� (Rattanasopha et al. 2012) have been associated with cleft lip and palate (CL/P) reflecting a conserved role for PDGF signaling in mammalian midface development. Interestingly NCC conditional loss of FGF receptor 1 (FGFR1) also results in craniofacial defects (Trokovic et al. 2003; Wang et al. 2013) indicating a requirement for both PDGF and FGF signaling in NCCs for craniofacial morphogenesis. Serum response factor (SRF) is a transcription factor critical for coupling actin dynamics and signaling pathways to gene expression OSI-930 (Posern and Treisman 2006; Olson and Nordheim 2010). SRF was identified as a regulator of the serum response in fibroblasts (Treisman 1987) and more recent work has focused on understanding the mechanisms of SRF specificity at the transcriptional level (Gineitis and Treisman 2001) particularly in regard to interactions with its two major cofactor families: ternary complex factors (TCFs) and myocardin related transcription OSI-930 factors (MRTFs) (Esnault et al. 2014). SRF can be activated in response to many extracellular stimuli including PDGF and FGF (Treisman 1996; Wang et al. 2004). However the specificity of SRF activation at a receptor level is usually unclear and a direct comparison of SRF function downstream of multiple RTKs has not been carried out. SRF is essential across many developmental and physiological contexts including mesoderm formation (Arsenian et al. 1998) cardiac development (Parlakian et al. 2004) angiogenesis (Franco et al. 2008) oligodendrocyte differentiation (Stritt et al. 2009) neuronal migration (Alberti et al. 2005) and circadian regulation (Gerber Rabbit polyclonal to AKAP10. et al. 2013). SRF was first implicated in neural crest development through an in situ hybridization screen (Adams et al. 2008) and OSI-930 neural crest conditional mouse mutants show defects in dorsal root ganglion (DRG) formation (Wickramasinghe et al. 2008) cardiac outflow tract development and mandible formation (Newbern et al. 2008). No facial clefting phenotypes have been previously reported and the role of SRF in midface development remains unknown. In the present study we statement that SRF is required for craniofacial development and responds differentially to PDGF and FGF signaling through selective interactions with MRTF and TCF cofactors. and double mutants (and (as a PDGF target gene (Table S2 “type”:”entrez-geo” attrs :”text”:”GSE61755″ term_id :”61755″GSE61755)..