Control of sex development

The process of sexual differentiation is central for reproduction of almost all metazoan, and therefore, for maintenance of practically all multicellular organisms. In sex development, we can distinguish two different processes, sex determination, that is the developmental decision that directs the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development. The second process known as sex differentiation takes place once the sex determination decision has been made through factors produced by the gonads that determine the development of the phenotypic sex. Most of the knowledge on the factors involved in sexual development came from animal models and from studies of cases in whom the genetic or the gonadal sex does not match the phenotypical sex, that is, patients affected by disorders of sex development (DSDs).Generally speaking, factors influencing sex determination are transcriptional regulators, whereas factors important for sex differentiation are secreted hormones and their receptors.

This review focusses on these factors and whenever possible, references regarding the ‘prismatic’ clinical cases are given.

Keywords: sex development, sex determination, sex differentiation, ovary, testis, disorders of sex development (DSD), bipotential state

Abbreviations: DSD, Disorders of sex development, Pax2, Paired Homeobox 2, Emx2, Empty spiracle homolog 2, Lhx9, Lim Homeobox protein 9, WT1, Wilms Tumour 1, GATA4, GATA-binding protein 4, SRY, Sex determining Region Y, SOX9, SRY- box 9, SF1/NR5A1, Steroidogenic Factor 1/Nuclear Receptor subfamily 5, group A, member 1, DAX1, Dosage sensitive sex reversal, Adrenal hypoplasia congenital critical region on the X chromosome gene 1, DMRT1, Doublesex and MAB3-Related Transcription factor 1, DHH, Desert Hedgehog, ATRX, Alpha Thalassemia, mental Retardation syndrome, X-linked, CBX2, Chromobox homolog 2, TSPYL1, Testis-specific protein Y-like-1, MAMLD1, Mastermind-Like Domain-Containing Protein 1, PGD2S, Prostaglandin D2 synthase, RSPO1, Root-plate specific Spondin 1, WNT4/FST, Wingless Type MMTV intergration site family, member 4/Follicostatin, FOXL2, Forkhead transcription factor, AMH/AMHR=MIS, Anti-Müllerian Hormone/Receptor=Müllerian Inhibiting Substance, HOXA, Homeobox A, Lim1/LHX1, Lim Homeobox protein 1, LH/CG, Luteinising Hormone/Corionic Gonadotropin, POF, Premature ovarian failure, ODG, Ovarian dysgenesis, FMR1, Fragile X Mental Retardation 1, DIAPH2, Diaphanous (dia) homolog 2, GDF9, Growth Differentiation Factor 9, BMP15, Bone Morphogenic Protein 15, NOBOX, Newborn Ovary Homeobox, FIGLA, Factor in Germ Line Alpha