Abstract
Genetic control of male or female gonad development displays between different groups of organisms a remarkable diversity of “master sex-determining genes” at the top of the genetic hierarchies, whereas downstream components surprisingly appear to be evolutionarily more conserved. Without much further studies, conservation of sequence has been equalized to conservation of function. We have used the medaka fish to investigate the generality of this paradigm. In medaka, the master male sex-determining gene is dmrt1bY, a highly conserved downstream regulator of sex determination in vertebrates. To understand its function in orchestrating the complex gene regulatory network, we have identified targets genes and regulated pathways of Dmrt1bY. Monitoring gene expression and interactions by transgenic fluorescent reporter fish lines, in vivo tissue-chromatin immunoprecipitation and in vitro gene regulation assays revealed concordance but also major discrepancies between mammals and medaka, notably amongst spatial, temporal expression patterns and regulations of the canonical Hedgehog and R-spondin/Wnt/Follistatin signaling pathways. Examination of Foxl2 protein distribution in the medaka ovary defined a new subpopulation of theca cells, where ovarian-type aromatase transcriptional regulation appears to be independent of Foxl2. In summary, these data show that the regulation of the downstream regulatory network of sex determination is less conserved than previously thought.
Highlights
Sex determination, the decision whether the bipotential gonad anlage will become a testis or an ovary, is a complex and tightly controlled developmental process
Its subordinated genes (SOX9, WT1, DMRT1, AMH, SF1, FOXL2) or signaling pathways (TGF-beta, WNT4/ beta-catenin, Hedgehog) have homologs in a much broader spectrum of species, including nonvertebrates, where they apparently are involved in sex determination
And in contrast to patched expression in mammals, ptch-2 expression was only detected at background levels throughout stages of testis development. This inconspicuous role for the Hedgehog signaling in gonad development and maintenance was apparent in real-time polymerase chain reaction (PCR) analysis
Summary
The decision whether the bipotential gonad anlage will become a testis or an ovary, is a complex and tightly controlled developmental process. Comparative studies on sex determination cascades of different organisms revealed a remarkable diversity of “master sex-determining genes” at the top of the genetic hierarchies, whereas downstream components surprisingly appeared to be evolutionarily more conserved and tend to converge upon the regulation of common effectors. Its subordinated genes (SOX9, WT1, DMRT1, AMH, SF1, FOXL2) or signaling pathways (TGF-beta, WNT4/ beta-catenin, Hedgehog) have homologs in a much broader spectrum of species, including nonvertebrates, where they apparently are involved in sex determination. These observations led to the emergence of the subversive stereotype that master sex-determining genes individually spark and orchestrate the irreversible action of uniform and integrated gender-specific pathways. We have used the medaka as a versatile model system to study gene regulatory interactions and their evolutionary conservation (Wittbrodt et al 2002; Herpin and Schartl 2009)
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