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WIREs Syst Biol Med
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Sex and the circuitry: progress toward a systems‐level understanding of vertebrate sex determination

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Abstract 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. WIREs Syst Biol Med 2012 doi: 10.1002/wsbm.1172 This article is categorized under: Biological Mechanisms > Cell Fates Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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Many genes may be involved in establishing a bipotential state in the early gonad. Balanced antagonistic signaling pathways, including fibroblast growth factor 9 (FGF9) and wingless‐related MMTV integration site 4 (WNT4), hold somatic precursor cells in an undifferentiated state. The transcriptome is highly active and complex during this window, which suggests that many more genes and pathways are involved in conferring this plasticity.

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Sexual fate of the XY gonad depends on the number of specified pre‐Sertoli cells (i.e., cells that are expressing SOX9 (SRY‐box containing gene 9) above a differentiation threshold) present in the gonad when the bipotential window closes. This critical timepoint appears to be set by the expression of ovarian pathway genes in the bipotential XY gonad. Once the ovarian pathway has progressed to a ‘point of no return’ (the ovarian canalization threshold, OCT; denoted as a red dotted line), the number of specified pre‐Sertoli cells in the XY gonad must surpass a threshold (the testis canalization threshold, TCT; blue dotted line) to direct testis development. If the number of pre‐Sertoli cells does not meet this threshold by this critical timepoint, the XY gonad full or partially sex reverses to an ovary or ovotestis. Variation in the expression of ovarian pathway genes in XY gonads among inbred strains may affect the duration of the bipotential window. For example, the higher expression or earlier onset of ovarian pathway genes in B6 XY gonads (dashed purple line) relative to 129S1 (solid purple line) may cause the bipotential window to close earlier in B6 (denoted by red triangle; compare to yellow triangle = critical timepoint in 129S1). In XX gonads, the ovarian pathway proceeds past the OCT and is canalized toward ovarian development.

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Sex determination within individual XY supporting cells depends on the level of Sox9 (SRY‐box containing gene 9) expression. (a) The complexity of Sox9 regulation points to its importance as the conserved regulatory hub of the testis differentiation pathway. Sox9 is expressed at basal levels early in both XY and XX gonads. 1. A pulse of Sry (sex‐determining region of Chr Y) expression activates the initial upregulation of Sox9 in XY somatic supporting cell precursors. Sox9 may or may not be involved in extinguishing Sry expression. 2. Following the initial activation by SRY, SOX9 is able to bind its own promoter with higher affinity than SRY and act in an autoregulatory feedforward loop. 3. Intercellular prostaglandin D2 (PGD2) and fibroblast growth factor 9 (FGF9) signaling pathways act as independent feedforward loops to amplify Sox9 expression downstream of Sry‐mediated activation. 4. Many other genes are likely to directly or indirectly regulate Sox9 expression or function, including unidentified genes underlying expression QTLs (eQTLs) on mouse Chromosomes 1, 5, 6, and 11. 5. Multiple genes associated with the ovarian differentiation pathway, including Wnt4 (wingless‐related MMTV integration site 4)/Rspo1 (R‐spondin homolog)/β‐catenin, Foxl2 (forkhead box L2), and the estrogen receptors ERα and ERβ, are likely to repress Sox9 expression to canalize the ovarian pathway. It is important to note that one or more of the genes underlying the Sox9 eQTLs could influence Sox9 expression indirectly by activating or repressing female pathway genes. (b) Within individual gonad supporting cells, sexual fate is likely to be a binary decision. The intracellular concentration of SOX9 most likely must reach a critical threshold (denoted by a red dotted line) relative to the underlying setpoint of the network before E11.5 to impose a testis‐specific state on the transcription network. Cells that fail to express SOX9 above this threshold adopt the alternative ovarian‐specific network state.

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Evidence for a transcriptional tug‐of‐war underlying sex determination. A coexpression network was estimated for a subset of 40 genes quantified in 68 XY gonad samples from a mixed F2 intercross of B6 and 129S1. Testis‐associated genes that are enriched in XY gonads at E11.5 are highlighted in blue, whereas ovarian genes are highlighted in pink, and genes with known roles in sex determination that are not expressed in a sexually dimorphic pattern at E11.5 are highlighted in yellow. Thick black edges represent more robust coexpression relationships (partial correlation coefficient ≥0.33), while thinner edges are less robust but still significant (partial correlation coefficient ≥0.25). (Reprinted with permission from Ref 7. Copyright 2009 Cold Spring Harbor Laboratory Press)

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Biological Mechanisms > Cell Fates
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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