The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10

Abstract

SUMMARYWaardenburg syndromes are characterized by pigmentation and autosensory hearing defects, and mutations in genes encoding transcription factors that control neural crest specification and differentiation are often associated with Waardenburg and related disorders. For example, mutations in SOX10 result in a severe form of Waardenburg syndrome, Type IV, also known as Waardenburg-Hirschsprung disease, characterized by pigmentation and other neural crest defects, including defective innervation of the gut. SOX10 controls neural crest development through interactions with other transcription factors. The MADS box transcription factor MEF2C is an important regulator of brain, skeleton, lymphocyte and cardiovascular development and is required in the neural crest for craniofacial development. Here, we establish a novel role for MEF2C in melanocyte development. Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes. We identify a transcriptional enhancer of Mef2c that directs expression to the neural crest and its derivatives, including melanocytes, in transgenic mouse embryos. This novel Mef2c neural crest enhancer contains three functional SOX binding sites and a single essential MEF2 site. We demonstrate that Mef2c is a direct transcriptional target of SOX10 and MEF2 via this evolutionarily conserved enhancer. Furthermore, we show that SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit, suggesting that MEF2C might serve as a potentiator of the transcriptional pathways affected in Waardenburg syndromes.

Endothelin signaling activates Mef2c expression in the neural crest through a MEF2C-dependent positive-feedback transcriptional pathway

“…1B-E). As previously described (Agarwal et al, 2011), the Mef2c-F1 enhancer was active in cranial and trunk neural crest populations at E9.5 (Fig. 1B).…”

“…We previously identified an enhancer from the Mef2c locus with activity in multiple neural crest lineages (Agarwal et al, 2011). This enhancer, referred to as Mef2c-F1, contains a conserved MEF2 consensus site important for autoregulation of Mef2c expression ( Fig.…”

“…This enhancer, referred to as Mef2c-F1, contains a conserved MEF2 consensus site important for autoregulation of Mef2c expression ( Fig. 1A; Agarwal et al, 2011), which we hypothesized might be a target of Endothelin signaling, given the possible links between Endothelin signaling and MEF2C expression and function (Agarwal et al, 2011;Miller et al, 2007;Verzi et al, 2007;Wu et al, 2006). To determine whether the Mef2c-F1 enhancer was regulated by Endothelin, we crossed Mef2c-F1-lacZ transgenic mice to Ednra and Ednrb knockout mice (Fig.…”

“…Studies performed in the mouse established a requirement for MEF2C for proper craniofacial and melanocyte development and, based on the observation that MEF2C and Endothelin signaling regulate several common downstream targets (Agarwal et al, 2011;Ruest et al, 2004;Verzi et al, 2007), suggested that MEF2C functions in the Endothelin signaling pathway in the neural crest. Similarly, mutation of the Mef2c ortholog mef2ca in zebrafish results in craniofacial defects due to disrupted neural crest development (Miller et al, 2007).…”

Establishing neural crest identity: a gene regulatory recipe

“…These animals also show loss of expression of Mitf and Dct. Mef2c is directly activated by Sox10, and subsequently cooperates with the latter to activate itself and possibly other targets (Agarwal et al, 2011). Data from amniotes suggest that melanocyte specification and differentiation mostly rely upon feed-forward transcriptional circuits involving Sox10 and other transcription factors expressed in precursor cells, resulting in the robust activation of melanogenic enzymes.…”