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Phosphorylation of a Master Transcription Factor in Human Organogenesis Regulates Developmental Fate
Author(s) -
Chen YenShan,
Nelson B
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.602.5
Subject(s) - testis determining factor , biology , genetics , transcription factor , gene , regulation of gene expression , microbiology and biotechnology , y chromosome
A seeming paradox is posed by metazoan gene‐regulatory networks (GRNs) that are robust yet evolvable. Insight may be obtained through studies of bistable genetic circuits mediating developmental decisions and in particular transcriptional thresholds governing cell‐fate decisions. We illustrate a general strategy to measure such thresholds by focusing on the genetic boundary between organization and dysgenesis. A model is provided by testis determination in therian mammals, which is initiated by SRY, a Y‐encoded architectural transcription factor. Mutations in human SRY cause gonadal dysgenesis leading to development of an XY female with primary amenorrhea ( Swyer syndrome ). Our study has focused on an inherited mutation in human SRY (R30I) previously identified in a fertile XY father and sterile XY daughter ( inherited Swyer syndrome ). We have demonstrated that this mutation markedly impaired phosphorylation of SRY within a PKA site N‐terminal to the HMG box. On transient transfection of human and rodent cell lines, the variant SRY exhibited reduced binding to the testis‐specific enhancer of principal target gene SOX9 ; gene‐regulatory activity was reduced by twofold relative to wild‐type SRY. To our knowledge, this is the first report of a human birth defect due to mutation of a PKA site within a lineage‐specific transcription factor. Our results and their clinical correlation provide novel evidence that the robustness of human testis determination requires regulated serine phosphorylation of SRY. Further, the twofold attenuation of transcriptional activity observed here is characteristic of diverse mutations in SRY associated with inherited Swyer syndrome—irrespective of molecular mechanism—and so defines the narrow transcriptional threshold of male gonadogenesis in human development. We speculate that such a tenuous sex‐specific genetic switch has evolutionary advantages via multi‐level selection as envisaged through the framework of sociobiology.