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Transcriptomic insight into molecular processes of light-induced rapid darkening of non-obligative cave dweller Oreolalax rhodostigmatus (Megophryidae, Anura) and their genetic basis of pigmentation strategy

ABSTRACT: O. rhodostigmatus are non-obligative cave dwellers, whose tadpoles keep albinistic phenotype in caves but rapidly darken in light within 24 hours. Their coloration system is an excellent model for exploring the processes and mechanisms of light-induced pigmentation and revealing the genetic adaptation for non-obligative cave dwelling due to complicated life history. Using comparative transcriptomics, we found that melanocyte MCC (including melanogenesis and melanocytes proliferation) was responsible for the rapid skin darkening in was activated in O. rhodostigmatus. Light exposure induced robust activation of growth signals (including growth factor signals, MAPK signal pathways and PIK3-Akt signal pathways) at transcriptional levels, which were likely the upstream activation signals of melanocyte MCC in O. rhodostigmatus tadpoles. These results evidenced that amphibians and mammals likely share similar regulatory signals for light-induced melanocyte MCC. The conservation of pigmentation mechanisms across lower vertebrates and mammals imply that knowledge based on simpler models could also provide implications for causations and therapies of human pigmentation disorders and pigmented tumors. In aspect of genetic adaptation, an in-frame deletion of four amino acids in the membrane/extracellular junctions of the second and third transmembrane domains of O. rhodostigmatus MC1R, the receptor for melanogenesis signal, was identified. This mutation increases the negative charge of the ligand pocket of MC1R and results stereo-tandem of three aspartate residues aligning towards its ligand pocket. The ligand pocket of O. rhodostigmatus MC1R resembles a trap for positively charged ligands (α-MSH and ACTH) and likely increases the ligands-dependent activity of MC1R, providing an explanation for the rapid MCC of O. rhodostigmatus in light. Meanwhile, increased negative charge of ligand pocket likely decreased the constitutive activity of MC1R, in in supporting the albinistic phenotype of cave dwelling tadpoles. Therefore, genetic change of MC1R explains, at least to some extent, how the pigmentation system of O. rhodostigmatus coordinates the capacity of rapid melanogenesis (or other types of pigment production) and pigment regression, a couple of seemingly contradictory coloration requirements. To our knowledge, this is the first study reporting the association between pigmentation phenotype adaptation and MC1R mutations in amphibians or in non-obligative cave dwellers.

ORGANISM(S): Oreolalax rhodostigmatus

PROVIDER: GSE106622 | GEO | 2018/06/07

REPOSITORIES: GEO

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Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.

Dataset Information

Transcriptomic insight into molecular processes of light-induced rapid darkening of non-obligative cave dweller Oreolalax rhodostigmatus (Megophryidae, Anura) and their genetic basis of pigmentation strategy

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