Factors Involved in Gonadal Differentiation
| Gene | Chromosomal localization | Expression | Function |
|---|---|---|---|
| ATRX (Alpha-thalassemia/mental retardation syndrome, Helicase 2, X-Linked) | Xq21.1 | Widespread | Nucleotide excision repair and initiation of transcription |
| CBX2 (Chromobox homolog gene 2; or M33 mouse homolog of) | 17q25.3 | Widespread | Regulation of homeotic genes. Represses WNT4 signaling |
| CITED2 (CBP/p300-interacting transactivator, with glu/asp-rich c-terminal domain, 2) | 6q24.1 | Widespread | WT1 and SF1 cofactor, regulating SRY expression in the gonad |
| COUP-TF2 (Chicken ovalbumin upstream promoter transcription factor 2), or NR2F2 (Nuclear receptor subfamily 2, group F, member 2) | 15q26.2 | Widespread | Transcription factor (orphan nuclear receptor) likely involved in mesenchymal-epithelial interactions |
| CTNNB1 (β-catenin) | 3p22.1 | Widespread | Upregulates WNT4, FST and FOXL2 |
| DAX1: DSS-AHC critical region on the X chromosome 1); or NR0B1 (Nuclear receptor subfamily 0, group B, member 1). | Xp21.2 | Gonads, pituitary, adrenals | Antagonizes SRY, SOX9. Essential for normal testicular and ovarian development |
| DHH (Desert hedgehog) | 12q13.12 | Sertoli cells (testis), Schwann cells (peripheral nerves) | Morphogenesis |
| DKK1 (Dickkopf, xenopus, homolog of, 1) | 10q21.1 | Widespread | Represses WNT4 binding to the LRP5/6 co-receptor |
| DMRT1 (Doublesex- and mab3-related transcription factor 1) | 9p24.3 | Gonads and several other tissues | Antagonizes FOXL2 |
| FGF9 (Fibroblast growth factor 9) | 13q12.11 | Gonads and several other tissues | Upregulation of SOX9 and downregulation of WNT4 |
| FGFR2 (FGF receptor 2) | 10q26.13 | Gonads and several other tissues | Upregulation of SOX9 and downregulation of WNT4 |
| FOG2 (Friend of GATA, gene 2, or ZFPM2: zinc finger protein multitype 2) | 8q23.1 | Widespread | Repression of DKK1 |
| FOXL2 (Forkhead transcription factor 2) | 3q22.3 | Gonads and eyelids | Antagonizes SOX9. Survival of meiotic germ cells |
| FST (Follistatin) | 5q11.2 | Widespread | Antagonizes Activins. Survival of meiotic germ cells |
| GADD45G (Growth arrest- and DNA damage-inducible gene, gamma) | 9q22.2 | Widespread | Phosphorylation of GATA4 |
| GATA4 (GATA-binding protein 4) | 8p23.1 | Widespread | Regulation of SRY expression |
| HHAT (Hedgehog acyltransferase) | 1q32.2 | Gonads | Two INHBB subunits form Activin B dimer, which induces vascular endothelial cell migration to the gonad |
| INHBB (Inhibin βB, Activin βB) | 2q14.2 | Gonads | Two INHBB subunits form Activin B dimer, which induces vascular endothelial cell migration to the gonad |
| JMJD1A; or KDM3A (Lysin-specific demethylase 3A) | 2p11.2 | Testis, ovary, kidney, lung, heart, brain, liver, skeletal muscle, pancreas, and spleen | Demethylases histone H3 (epigenetic regulation by modification of chromatin conformation) |
| MAP3K1 (MAP/ERK Kinase Kinase 1; MEKK1; MAPKKK1; MEK Kinase) | 5q11.2 | Widespread | Phosphorylation of GATA4 |
| MAPK14 (Mitogen-activated protein kinase 14; or p38-MAPK) | 6p21.31 | Widespread | Phosphorylation of GATA4 |
| NR5A1 (Nuclear receptor subfamily 5, group A, member 1, also SF1: Steroidogenic factor 1, or AD4BP: Adrenal 4 binding protein, or FTZF1: Fushi tarazu factor homolog 1) | 9q33.3 | Gonadal ridges, adrenal gland primordia, hypothalamus and pituitary | Transcriptional regulation of several genes (SRY, SOX9, STAR, steroid hydroxylases, aromatase, AMH, DAX1 and many other) |
| PDGFB (Platelet-derived growth factor, beta polypeptide) | 22q13.1 | Endothelial cells | Increase in cell proliferation in the gonadal interstitial tissue |
| PDGFRA (PDGF receptor α) | 4q12 | Gonadal interstitial cells and several other tissues | Increase in cell proliferation in the gonadal interstitial tissue |
| PTGDS (or PGDS2: Prostaglandin D2 synthase) | 9q34.3 | Gonads and several other tissues | Synthesis of prostaglandin D2 (PGD2), upregulation of SOX9 and its nuclear translocation |
| RSPO1 (R-spondin family, member 1) | 1p34.3 | Gonads and skin | Upregulates WNT4 by sequestering the transmembrane E3 ubiquitin ligases ZNRF3 and RNF43. Cooperates with WNT4 signaling, by antagonizing DKK1, to stabilize β-catenin and FST |
| SOX8 (SRY box 8) | 16p13.3 | Gonads and several other tissues | Transcriptional regulation of SOX9, in cooperation with SF1 |
| SOX9 (SRY box 9) | 17q24.3 | Testis, cartilage | Triggers testis differentiation, and regulates several testis-specific genes |
| SOX10 (SRY box 10) | 22q13.1 | Gonads and several other tissues | Transcriptional regulation of SOX9, in cooperation with SF1 |
| SP1 (Specificity protein 1) | 12q.13.13 | Widespread | Regulation of SRY expression |
| SRY (Sex-determining region on the Y chromosome) | Yp11.31 | Male gonadal ridge | Regulates SOX9 and triggers testis differentiation |
| VEGFA (Vascular endothelial growth factor A) | 6p21.1 | Mesenchymal cells of the gonadal ridge and other organs | Induces vascular endothelial cell migration to the gonad |
| WNT4 (Wingless-type MMTV integration site family, member 4) | 1p36.12 | Gonads and several other tissues | Induces β-catenin and silences FGF9 and SOX9 by binding to Frizzled receptor |
| WT1 (Wilms tumor associated gene 1) | 11p13 | Urogenital ridge derivatives | Transcriptional regulation and post-transcriptional stabilization of SRY |
| ZNRF3 (Zinc finger and ring finger protein 3) | 22q12.1 | Widespread | Inhibition of WNT signaling by targeting Frizzled receptor for degradation by ubiquitination and increased membrane turnover |
From: Sexual Differentiation
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