Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Hormones in male sexual development Serge Nef and Luis F. Parada1 Center for Developmental Biology, University of Texas, Southwestern Medical Center, Dallas, Texas 75235–9133, USA A fascinating aspect of development is the potential of genital ridge. In mice, the genital ridges are visible at sexually undifferentiated embryos to generate male or embryonic day 10 (E10) and are composed of somatic female individuals. Our knowledge of mammalian sex cells from the mesonephros and migratory primordial determination and differentiation has increased steadily germ cells originated from extraembryonic mesoderm in in recent years. After presenting a brief overview of go- the yolk sac near the junction of the hindgut and allan- nadal development and sexual determination, this ar- tois (Ginsburg et al. 1990). ticle reviews recent findings concerning male sexual dif- In mammals, four genes are known to be required for ferentiation. In particular, we focus on the three essen- development of bipotential gonads (Fig. 1): (a) the orphan tial hormones secreted by the testes—androgens, MIS, nuclear receptor Steroidogenic factor-1 (SF1 or Ftz-F1; for and Insl3—all of which cause male-specific development review, see Parker 1998), (b) Wilms tumor-associated of the bipotential reproductive system. gene (WT1; Kreidberg et al. 1993), a zinc finger DNA– In mammals, genetic sex is determined by inheritance binding protein, (c) Lhx1 (also known as Lim1), and (d) of either an X or Y chromosome from the male gamete. Lhx9, two LIM class homeobox proteins (Shawlot and The initial stages of gonadal and genital development of Behringer 1995; Birk et al. 2000). Mice with a homozy- male and female embryos are indistinguishable by mor- gous disruption in any one of these genes lack gonads. phological criteria. In females, Mu¨llerian ducts give rise Once the gonads are formed, the pivotal event in male to uterus, fallopian tubes, and proximal vagina, while in sexual differentiation is expression of the SRY gene (sex males, Wolffian ducts develop into multiple reproduc- determining region of the Y chromosome). SRY is nec- tive organs including vas deferens, seminal vesicles, and essary and sufficient to initiate the male development epididymis. The classic experiment of Jost (Jost 1947; cascade (Koopman et al. 1991). SRY encodes a high-mo- Jost 1953) demonstrated that female differentiation oc- bility group (HMG) box-transcription factor and, similar curs irrespective of the genetic sex in the absence of tes- to other HMG-transcription factors, binds preferentially ticular hormones. Current studies indicate that male dif- to a consensus DNA sequence and causes DNA bending ferentiation requires the secretion of three testicular hor- (Grosschedl et al. 1994). The physiological target genes mones. Mu¨llerian-inhibiting substance (MIS), also for SRY/Sry remain unknown, but potential candidates named Mu¨llerian-inhibiting factor (MIF) or anti-Mu¨lle- including Sox9, SF-1, DMRT1, GATA-4, Dhh, and rian hormone (AMH), produced by fetal Sertoli cells in- testatin, are up-regulated during testicular differentia- duces regression of the Mu¨llerian ducts. Testosterone, tion (for review, see Roberts et al. 1999b; Swain and Lov- produced by Leydig cells, promotes development of ell-Badge 1999). SRY/Sry triggers differentiation of the Wolffian duct derivatives and masculinization of the ex- supporting cell lineage into Sertoli cells (Burgoyne et al. ternal male genitalia. Finally, insulin-like 3 (Insl3) me- 1988; Palmer and Burgoyne 1991). diates transabdominal testicular descent into the scro- The factors produced by Sertoli cells that influence tum (Nef and Parada 1999; Zimmermann et al. 1999). In differentiation of the steroidogenic cell lineage into Ley- females, differentiation occurs when the absence of MIS dig cells and the germ-cell lineage into prospermatogo- allows development of the Mu¨llerian structures, the lack nias remain unknown. Another major function of Sertoli of androgens permits degeneration of Wolffian ducts, and cells is to sustain germ cells during development and the absence of Insl3 maintains the gonads in the abdo- spermatogenesis. They do so by forming tight cell–cell men. contacts between germ cells and providing factors nec- essary for growth and differentiation. Factors mediating interaction between Sertoli cells and germ cells act at Gonadal and sexual determination close range, and one potential candidate is Desert hedge- The gonads originate from thickening of the ventrolat- hog (Dhh). Male mutants for Dhh are infertile because of eral surface of the embryonic mesonephros called the the absence of sperm (Bitgood et al. 1996). Mutant testes show reduced weight from E18.5, and later stages display germ cell deficiency and blockade of spermatogenesis. 1Corresponding author. The early male-specific expression of Dhh, as well as the E-MAIL [email protected]; FAX (214) 648-1960. Article and publication are at www.genesdev.org/cgi/doi/10.1101/ mutant phenotype, suggests a role in male gonadal dif- gad.843800. ferentiation. GENES & DEVELOPMENT 14:3075–3086 © 2000 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/00 $5.00; www.genesdev.org 3075 Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Nef and Parada Figure 1. Summary describing known molecular and cellular interactions during gonadal induction, gonadal differentiation, and sexual differentiation. This figure has been adapted from a figure by P. Koopman (Koopman 1999). DMRT1 is another gene involved in testis differentia- mining period. In testis, Dmrt1 is expressed in germ cells tion. Humans with hemizygocity for the distal portion of and Sertoli cells (Raymond et al. 1999). Raymond et al. the locus 9p24.3 where DMRT1 has been mapped display (2000) have recently shown that Dmrt1 is required for defective testicular development and consequent 46, XY testis but not ovarian differentiation. Male mutant mice feminization (Crocker et al. 1988; Bennett et al. 1993; for Dmrt1 are viable but infertile, with hypoplastic tes- Raymond et al. 1998). The DMRT1 gene encodes a zinc tes, because of disorganized seminiferous tubules and ab- finger–like DNA-binding protein and is expressed very sence of germ cells. Sertoli cell morphology, number, early in a sex-specific manner in male gonads of all the and gene expression are also abnormal. These data indi- classes of vertebrates, regardless of the sex-determining cate that Dmrt1 is necessary for the survival and differ- mechanism (chromosomal or environmental). In mice, entiation of germ cells and Sertoli cells. It will be inter- Dmrt1 is expressed in genital ridges of both sexes and esting to determine if germ-cell death in Dmrt1 mutant then becomes testis specific at the end of the sex-deter- mice is an autosomous or nonautosomous defect caused 3076 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press New insights into mammalian male sexual differentiation by a failure of Sertoli cell differentiation. Cell-specific MIS signaling is mediated by the single transmem- deletion of the Dmrt1 gene in Sertoli cell or germ cells brane–spanning serine/threonine kinase receptors type I employing the Cre/lox system will provide valuable in- and II. The MIS type II receptor binds MIS (Mishina et al. formation concerning this question. 1999) and then recruits type I receptor to form tetrahet- DAX1 has also been implicated in testis differentia- eromers. Downstream signaling occurs when receptor I tion. DAX1 encodes an orphan nuclear receptor and is phosphorylated by the MIS type II receptor. In contrast maps to the X chromosome. In humans, duplication of to MIS receptor type II (Baarends et al. 1994; di Clemente the DAX1 locus causes male to female sex reversal (Bar- et al. 1994), the type I receptor remains unidentified. doni et al. 1994; Muscatelli et al. 1994; Zanaria et al. Recently, Goue´dard and colleagues (2000) provided in 1994) and, for this reason, has been proposed as an ovar- vitro evidence that bone morphogenic protein (BMP) ian-determining gene (Bardoni et al. 1994). However, XY type IB receptor (BMPR-IB) interacts with MIS receptor transgenic mice with multiple copies of Dax1 do not type II in a ligand-dependent manner and transduces sig- display male-to-female sex reversal. In contrast, XX mice nals through the Smad1 pathway. Another recent report with an Sry transgene fail to initiate testis development implicates ␤-catenin/LEF1 transduction pathway in me- in mice carrying multiple copies of Dax1, indicating that diating MIS action (Allard et al. 2000). In vivo and in Dax1 can antagonize Sry-mediated sex conversion vitro MIS application leads to an accumulation of cyto- (Swain et al. 1998). Furthermore, in Dax1 mutant mice, plasmic ␤-catenin in mesenchymal cells. Further work ovarian development is not affected, yet spermatogene- will be needed to confirm and clarify the roles played by sis is blocked in the male (Yu et al. 1998). Thus, Dax1 is these different transduction molecules in MIS signaling. more likely an “antimaleness” gene rather than an ovar- Male Mis gene knockout mice develop as pseudoher- ian-determining gene (Parker and Schimmer 1998; Swain maphodites, with retention of Mu¨ llerian structures. et al. 1998; Yu et al. 1998). However, in contrast to humans who exhibit retention of the testes within the abdominal cavity (Josso and di Clemente 1997), mouse testes are normally descended into the scrotum, with infertility being caused by the Sexual differentiation superimposition of male and female reproductive organs, Once gonads have differentiated into testes, the secre- blocking sperm delivery (Behringer et al. 1994). tion of testicular hormones is sufficient to promote mas- MIS is also produced at low levels in adult testes, sug- culinization of the embryo. The male phenotype relies gesting a functional role for this hormone in the mature on the secretion of three testicular hormones: MIS, tes- gonad (Tsafriri et al.