Wiley Interdiscip Rev Syst Biol Med - Sex and the circuitry: progress toward a systems-level understanding of vertebrate sex determination.

Tópicos

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Resumo

In vertebrates, the gonad arises as a bipotential primordium that can differentiate as a testis or ovary. Cells are initially primed to adopt either fate by balanced antagonistic signaling pathways and transcription networks. Sexual fate is determined by activating the testis or ovarian pathway and repressing the alternative pathway. A complex, dynamic transcription network underlies this process, as approximately half the genome is being transcribed during this period, and many genes are expressed in a sexually dimorphic manner. This network is highly plastic; however, multiple lines of evidence suggest that many elements of the pathway converge on the stabilization or disruption of Sox9 expression. The single gene mutational approach has led to the identification of ~30 additional genes involved in vertebrate sex determination. However, >50% of human disorders of sexual development (DSDs) are not explained by any of these genes, suggesting many critical elements of the system await discovery. Emerging technologies and genetic resources enable the investigation of the sex determination network on a global scale in the context of a variable genetic background or environmental influences. Using these new tools we can investigate how cells establish a bipotential state that is poised to adopt either sexual fate, and how they integrate multiple signaling and transcriptional inputs to drive a cell fate decision. Elucidating the genetic architecture underlying sex determination in model systems can lead to the identification of conserved modules correlated with phenotypic outcomes, and critical pressure points in the network that predict genes involved in DSDs in humans.

Resumo Limpo

vertebr gonad aris bipotenti primordium can differenti testi ovari cell initi prime adopt either fate balanc antagonist signal pathway transcript network sexual fate determin activ testi ovarian pathway repress altern pathway complex dynam transcript network under process approxim half genom transcrib period mani gene express sexual dimorph manner network high plastic howev multipl line evid suggest mani element pathway converg stabil disrupt sox express singl gene mutat approach led identif addit gene involv vertebr sex determin howev human disord sexual develop dsds explain gene suggest mani critic element system await discoveri emerg technolog genet resourc enabl investig sex determin network global scale context variabl genet background environment influenc use new tool can investig cell establish bipotenti state pois adopt either sexual fate integr multipl signal transcript input drive cell fate decis elucid genet architectur under sex determin model system can lead identif conserv modul correl phenotyp outcom critic pressur point network predict gene involv dsds human

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