Testis determination: soft talk and kinky sex Robin LovelI-Badge M e d i c a l Research Council, L o n d o n , UK The activity of the Y-linked Sty gene during a critical period of gonadal differentiation is the normal trigger for testis determination and subsequent male development in mammals. This gene encodes a DNA-binding protein of the HMG-box class. It has been shown to induce a dramatic kink in target DNA-binding sites, which allows for much speculation on how the gene functions to regulate testis-specific gene expression. It is also clear that cell interactions are vital to its mode of action, and generally in the process of gonadal differentiation. Current Opinion in Genetics and Development 1992, 2:596-601

Introduction Two aspects of manm~alian testis detem~ination are considered in this review. First, the role of cell-cell interactions in the development of the gonad and second, how the testis-deternqining gene functions at a molecular level In manm~als, the Y chromosome is male determining [1-3], but although this chromosome is present from fertilization, the phenotypic sex of the embryo is not apparent until after the gonads have begun to develop as either testes or ovaries [4]. SD; the gene on the Y chromosome that is responsible for male development [5"'], is not expressed until about 10.5 days post coitum (dpc) in the mouse, coincident with the major period of organogenesis [6]. Sly acts specifically within cells of the developing indifferent gonads (or genital ridges) to cause their differentiation along the testicular pathway. Although the product encoded by Sp'I, is a DNA-binding protein [7"] and must act cell-autonomously, testis differentiation is critically dependent on cell interactions. Furthem~ore, many subsequent steps leading to the final sexual phenot3,pe depend on cell interactions and cell to cell signalling mediated by growth factors and steroid hormones..As the latter act systemically, many (potentially all) cell types throughout the organism can be aifected. By this mc,~ans the sex-determination signal is exported from the gonads. This can be contrasted to the situation found in both Drosophila and CaenorhabditL~" elegalzs, the two species for which we know most about the genetic hierarchies leading to the development of male and female characteristics (see [8"] for a recent review). There are many differences in the underlying mechanisms between these two species, but in both cases the primary sexdetermining signal, the X:autosome ratio, serves very early on in development to activate a cascade of sexdetermining genes within every somatic cell. These genes

in turn regulate the activit~ of the sex-specific differentiation genes responsible for the male or female phenotype. In Drosophila, all of the established pathway depends on cell-autonomously acting genes (much of the regulation occurring at the level of splicing) and there appears to be no requirement for cell--cell interactions. In C. elegans, the pathway includes at least one extracellular step, which involves a short range interaction between a putative ligand and receptor [9*]; however, this may simply serve as a safeguard to correct mistakes in a finely balanced system, with the somatic cell sex essentially established early on by the cell-autonomously acting genes [i0]. Therefore, in Drosophila and C. elegans, as in mammals, all cells are potentially alTected by the sex-determination process. This is not surprising in Drosophila and C. elegans as sex detemlination is tied to the mechm~sm of X-chromosome dosage compensation which must occur in all cells, whereas in most mamn~als the two processes appear unconnected (there is evidence for an X:autosome ratio elTect on non-gonadal sexually dimorphic structures in marsupials [11]). The manlmalian system appears to be more flexible and presumably evolved from the non-genetic, environmental mechanisms found in many lower vertebrates [12].

Cell--cell interactions Our current working l~}9othesis assumes that there are four cell lineages that make up the developing manlmalian gonad, each of which is effectively bipotential [13-151. These comprise the germ cells, which migrate iqto the genital ridge between the tenth and eleventh day of development, and three somatic cell types: the supporting cell precursors, which give rise to Sertoli cells in the male and follicle cells in the female; steroid-producing cell precursors, which give Leydig cells in the male

Abbreviations dpc--days posl coitum; HMG--high mobility group; IHF--integration host factor; SI--Steel; W--dominant whRe-spotOng. 596

(~) Current Biology Ltd ISSN 0959-437X

Testis determination: soft talk and kinky sex LovelI-Badge and theca or interstitial cells in the female; and connective tissue cells, which include those that give vascular tissue (particularly prominent in tile testis), mnica and peritubular myoid cells in the testis, and tunica and stromal cells in the ovary.

Germ cells In manamals, the interactions involving germ cells are comparatively well documented. First, in the migratory period the changing substrates provided by the cells of tim hind gut and dorsal mesentery, subsequently by cells of the mesonephros and finally by those of the genital ridge itself are necessary for the survival, proliferation and migration of the gema cells, lmpo~vmt components of this interaction are tile products of the Steel (SI), and dominant white-spotting (W) genes (which encode mast cell growth factor and its receptor c-kit, respectively) [16,17}. After entering the genital ridge the germ cells have two possible fates dependent on gonadal environment. In a testis, the germ cells enter mitotic arrest at about 13 dpc, resuming mitosis in spermatogonial stages after birth. In an ovary, the germ cells enter meiotic arrest over a period of two to three days from about 13.5dpc, remaining in this state until the oocytes complete maturation and ovulate post puberty. The chromosomal sex of the germ cells is irrelevant as XY germ cells can give oocytes and XX germ cells can give spermatogonia in chimaeras and in some cases of sex reversal [18,19]. Formation of oocytes is the default pathway as germ cells failing to colonize the developing testis in a male embryo can be found in meiotic arrest in, for exanlple, the adrenals [18]. Germ-cell sex is therefore determined according to the cellular environment. Possible mechanisms include: a cell surface or secreted molecule made by the Sertoli cells that causes gema cells to arrest in mitosis; a secreted factor made by the germ cells themselves, which only accumulates at high enough concentrations when the germ ceils become surrounded by Sertoli cells arranged in epithelial 'cords'; or a general external meiosis-inducing factor excluded from the interior of the cords by the epithelialization. There is no obvious return signal from the germ cells to the somatic cells that is required for testis development. Testes form normally in mice that are mutant at loci such as W o r SI and which completely lack germ cells in the genital ridge [6,18,20]. However, germ cells are required for correct development of ovaries. In their absence, follicle cells fail to organize and the ovary degenerates into a streak gonad. As we do not "know of any early markers that could indicate follicle-cell differentiation, it is not possible to say if ovarian determination is compromised. One attractive hypothesis is that germ cells entering meiosis provide an ovarian-inducing signal, however, preliminary attempts to address this question suggest that this is not the case (PS Burgoyne, R Lovell-Badge, unpublished data).

Somatic cells The origins of tile somatic-cell Wpes are much less well understood. The genital ridge arises as a thickening on the ventral side of the mesonephros, which itself is derived by inductive interactions within intermediate mesoderm. It is believed that there are contributions to the genital ridge from both the coelomic epithelium (tile layer of cells lining the body cavity) and from the underlying mesenchyme of the mesonephros. Tile former may give rise to the supporting cell precursors through epithelial-mesenchynaal transition, and the latter to myoid and interstitial cells (see below). There may ,also be contributions from the mesonephric ducts although morphological data suggests that they give rise to the rete part of the gonad (extragonadal tubules) [ 15,21].

Tile study of chimaeras and mosaics composed of XX and XY cells indicates that for a testis to develop a critical proportion of somatic cells in the genital ridge have to be XY [19]. This is in the order of 25% but is dependent on genetic strain. If tile proportion of XY cells is too low, an ovary or occasionally an ovotestis develops. The critic-al cell Wpe is probably the supporting cell precursor. This notion comes from experiments conducted by Burgoyne and colleagues [22,23"] who found that the different cell types within the testes of ~-X ,--+ X"Y chimaeric male mice were represented by proportions of ~ and XY cells that were similar to the proportions found through the rest of the chimaera, with the notable exception of the Sertoli cells. The latter were almost exclusively XY, indicating that the testis-determining gene must act cell-autononaously within the supporting cell precursors to divert their fate along the Sertoli cell pathway. The fact that S~3pencodes a DNA-binding protein provides a molecular explanation for this result. However, a few XX Sertoli cells were found suggesting that subsequent steps in Sertoli-cell differentiation can occur by a non-cellautonomous mechanism (also see [24,]). Some female chimaeras were also examined, but in these, the proportion of XY to XX follicle cells was the same as for other cell types in the animals [24.,25-]. But should not the XY cells be Sertoli cells? Tile fact that they were not suggests that Sp3, cannot exert its effect solely by cell-autonomous action. One way of reconciling all the chimaera data is to propose that S*], initiates Sertolicell differentiation, and regulates tile expression of ,an extracellular molecule (ligand or receptor). If sufficient nt, mbers of these pre-Sertoli cells are present ( > 25% of the supporting cell precursor population), dley will be able to induce themselves, through the action of this extracellular molecule, to continue along the Sertoli cell pathway. This type of auto-induction or 'community effect' has been described for other differentiating systems

[26}. The timing of Sty expression appears to be critical in that Y chromosome variants known to induce testis cord formation relatively late can fail to induce it at all in certain genetic backgrounds [27-',28,29]. The latter have been proposed to carry precocious ovarian-determination genes (implying that this process is as active as

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Pattern formation and developmental mechanisms

testis detem~ination). However, this limited window of opportunity is reminiscent of induction e v e n t s where both ability to induce and respond are short-lived [26]. Possibly it is the receptor (or ligand) for the SDqnduced extracellular molecule required for the 'autoinduction' effect proposed above that is limiting the response. If this is the case, there is no need to propose all active earl}, ovarian-detemlination step. Recent data from Buehr and Mckqren [30"] suggest that other cell types are also required for correct Sertoli-cell and testicular differentiation. The authors found that genital ridges from l l . 5 d p c ,-X~"embryos could not foml testes when cultured by themselves, despite the fact that this is where all the So,expressing cells are found [6]. Tile embryos did, however, produce testes when cultured together with the s~mle age mesonephros from either XY or XX embryos. When co-cultures using labelled mesonephros were done, Buehr and McLaren found that cells migrated from this tissue into the genital ridge. These migratory cells had become some interstitial cells mad tile peritubular myoid cells that line the Sertoli cell cords. It is not clear whether tile pre-Sertoli cells require the myoid cells to maintain and continue their differentiation, or simply for their organizatio,a into cords (for example, by supplying the appropriate basement-membrane components). It is therefore import.ant to determine if the pre-Sertoli cells revert to tile follicle-cell pathway in the absence of myoid cells, kalti-Mffllerian hormone, which should be specific to Sertoli cells at this stage, may be an appropriate marker to use. Its expression might, however, depend on the maintenance of appropriate cell contacts as Sertoli cell lines do not seem to express it. The myoid cells probably depend on tile presence of Sertoli cells for their ovm differentiation, as do the Leydig cells that begin to produce testosterone at about 13 dpc ~ter the cords have R)rmed.

Molecular

aspects of Sry function

How does SD~ exert its affect at a molecular level? Transcripts are present in mouse genital ridge cells for a period of about 36h prior to overt testis cord formation [6]. As Sertoli cells dMde fai,-ly rapidly, it is uniikely that SRY protein will persist at significant levels for much longer than this. So it appears that its activity is not required for any long-term maintenance of gene expression. This is also consistent with the notion that it is required only during a short window of opportunity.

HMG b o x e s

SRY was one of tile first members of a now rapidly expanding group of DNA-binding proteins united by possession of a domain referred to as an HMG box. Tile latter was first described as a region of Ilomology between high mobility group (HMG) non-histone proteins, such as HMG1, and hUBF, which is a cofactor of RNA polymerase 1 required for ribosomal RNA transcription [31]. The forme," are ubiquitous highly abundant chromatin-associated proteins that bind DNA without apparent sequence specificity [32"]. Despite being associated with its target genes, hUBF has no clear c o n s e n s u s DNA-sequence-motif to which it binds, and its interaction with DNA is fairly weak [31]. There are a number of other DNA-binding proteins of this sort that can be loosely grot, ped together by their properties of having little or no sequence specificity, being expressed ubiquitousl}, and tending to have more than one HMG box. SRY, however, falls into a second group, the members of which often show highly restricted tissue distribution, bind to specific sequences at high afl'inities and only have a single HMG box [33]. The two best characterized nlembers of this class are TCF1 and TCFI¢* (or LEF-1)

Table. 1. Comparison of the properties of the HMG1 and SRY proteins. HMG1

SRY

Very abundant

Very low abundance

Ubiquitous

Tissue specific

Two HMG boxes; dimer?

One HMG box; monomer only

No binding to linear DNA

Binds linear DNA with sequence specificity (consensus motif: AACAAT); bends DNA on binding, approximately 130°

Binds cruciform 1 DNA with no sequence specificity

Binds cruciform DNA with no sequence specificity 2

Contacts minor groove

Contacts minor groove

1Cruciform DNA (made either with four oligonucleotides or with an inverted repeat) has two angles of 120 ° and two of 60 °. 2SRY binds cruciform and AACAAT linear DNA at similar affinities (10 - 9 M-1). Data taken mostly from (Bianchi et aL, unpublished data) [37"'].

Testis determination: soft talk and kinky sex that are expressed in lymphoid cells and are involved in transcriptional regulation of, for example, T-cell-specific genes such as CD3 and TCRez [34,35]. All these factors interact with DNA through the HMG box, which is approximately 79 m-nino acids in length. Mutations in the HMG box of SRY have been associated with cases of sex reversal in humans that lead to XY females [7,36]. In vitro DNA-binding studies have also shown that the box is sufficient for the DNA binding of hUBF, LEF-1 and SRY to target sequences [31,37°°,38]. SRY has been shown to bind the s,'mae target sequence (AACAAAG) as TCF1, but the sequence AACAAAT is more likely to be the highest affinity site for both human and mouse SRY (VR Harley et aL, unpublished data)[37°.]. However, as yet no target gene has been identified for SRY. The gene for anti-MLillerian hormone, which has always seemed a reasonable candidate for a direct target, partly because of its known masculinizing effects in Freemartins, in t,itro and in transgenics, is not expressed with any obvious overlap with S~3~[39°.]. Also, as mentioned above, interaction of Se,'toli cells with other cell types may be required for its expression.

LovelI-Badge

the polll transcription complex to bind, or it could allow binding of other transcription factors, or allow two such factors to interact with each other. Alternatively, it could o p e n a domain (or loop) by freeing it from general repressors. Cotransformation studies with LEF-1 and a target gene construct have shown that by itself SRY has only weak activation properties [37°°,40"°]. This is consistent with the idea that it permits other specifc factors to activate transcription. When considering this gene fanaily as a whole, there are often other domains associated with the HMG box that are likely to be required for activation or interaction with other proteins. However, when mouse and human S~7/SRY sequences are compared there is no homology outside the HMG-box, and there seems to be no obvious activation domain in either, as based on sequence comparisons with "known transcriptional activators [42,43]. SRY could act by blocking the binding of another factor, although the simple act of bending the DNA through 130 ° could be sufficient to cause an effect on transcription.

Conclusion DNA bending Two recent studies have addressed in greater detail the interaction of HMG box-containing proteins with DNA. Grosschedl and colleagues [ 4 0 " ] have shown that both LEF-1 and SRY induce a dr,-maatic bend in target DNA on binding to it. Similar results have also been found for SRY by M Bianchi and his colleagues (personal communication). This bend is in the order of 130 °, which is more than for any other known transcription factor, although the Escherichia coil integration host factor (1HF) bends DNA by 140 ° [41]. Bianchi [32] had prevkxisly shown that HMG1 binds to fou,-way DNA junctions and crociform DNA structures at much higher affinities th:m it does to linear DNA. These cruciform structures, which may be artificially constructed by using four synthetic oligomers, also form at inverted repeats and at Holliday junctions during recombination. They have two angles of 60 ° and two of 120 ° and HMG1 is thought to bind to the former, which woulcl be equivalent to a bend of 120 = in linear DNA. Bianchfs recent results also show that SRY will bind the smile cruciform structures as HMG1, without sequence specificity and with affinities as high as its binding with AACAAT motig in linear DNA (personal communication). He suggests that probal)ly all HMG-boxes have this abilit-y to bind structural DNA, and th:lt bincling linear DNA is an extra property of the SRY/LEF1 class (see Table 1 ). What does this all mean? While SRY appears to bincl the same structures as HMG1, it seems unlikely that it would do so within the context of the nucleus as HMG1 is a highly abundant protein, and m w therefore be assumed to occupy all such sites. SRY is therefore likely to bind only its free specific target sequences in linear DNA. This binding will then induce a dramatic kink of 130 °. Such a kink could have one of several erects. For example, it could regulate target gene expression by directly allowing

If this review serves any purpose, it is to reveal how little we Mlow about nlammalian testis determination. SDp is clearly the key gene, but we do not "know how it affects the expression of other genes required for Sertolicell differentiation, or indeed whether it is an activator or repressor, or functions instead by altering the accessibility of other factors to chromatin domains. We will probably need to rely on non-predictive methods, such as genetic analysis to more fully characterize the cellular interactions involved in gonad formation, if we are ever going to understand the pathway or network of gene activity.' leading to testis formation.

Acknowledgements I would like to thank I?,lanche Capri and Shanthini Sockanathan for their critical reading o f the mant,scripl.

References and recommended reading Papers of particular interest, published vdthin tile annual period of review, have been highlighted as: • of special interest o. of outstancling interest I.

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JACOBS PA, STRONG JA: A Case of Human lntersexuality Having a Possible XXY Sex-determining Mechanism. Na. lure 1959, 183:302-303.

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WEI£IIONS\VJ, RUSSEH.LB: The Y Chromosome as the Bearer of Male Determining Factors in the Mouse. Proc N a t l A c a d Sci US/! 1959, 45:560-566.

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JOST A, VIGIER B, PR~N J, PERCHEIZETJP: Studies on Sex Differentiation in Mammals. Recent Prog Horm Res 1973, 29:1-41.

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MERCHANq'-LAR/OSH, TAKETO T: Testicular Differentiation in Mammals Under Normal and Experimental Conditions. f Electron Microsc Tech 1991, 19:158-171.

KOOI'blANP, GUBBAY J, VIVbM'q N, GOODFELLOW P. LOkrEIa.B,mGE R: Male Development of Chromosomally Female Mice Transgenic for SO: Nature 1991, 351:117-121. The finad proof that SO, is the testis-detemlining gene ,and, moreover, the only gene from chromosome Y needed for normal male developmen,.

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BURGOYNEPS, BUEHR M, KOOPMAN P, ROSSANTJ, McL,WaNEA: Cell Autonomous Action of the Testis-determining Gene: Sertoli Cells are Exclusively XY in XX X~t' Chimaeric Mouse Testes. Det,elopment 1988, 102:443-450.

5. ••

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KOOPMANP, MONSTERBERGA, CAPF.I.B, VI%q2MNN, LOVEU.-BADGI: R: Expression of a Candidate Sex-determining Gene during

Mouse Testis Differentiation. Nature 1990, 348:450--452. 7. ••

l~dlLE-YVR, JACKSON D, HEXTAI.L P, HA~.q~.INSJR, BERKO\qTZ GD, SOCKANATHANS, LOVELL-BADGER, GOODFELLOWPN: DNA Binding Activity of Recombinant SRY from Normal Males and XY Females. Science 1992, 255:453-456. This paper describes some of the DNA-binding properties of SRY protein, and also pro\ides a molecular explanation for the cases of XY sex reversal where flaere are amino-acid substitutions within the SRY H/riG-box. 8. HODGKINJ: Genetic Sex Determination, Mechanisms and • Evolution. Bioe.wa).~ 1992, 14:253-261. A recent review of the sex detemlination in C elegan.~ Dro.spbila attd the mouse, concentrating on evolutionary concepts. 9. •

HUNTI:'RCP, WOOD W'B: Cell Interactions in C. elegans Sex Determination: Genetic Evidence from Mosaic Analysis of the Masculinizing G e n e her-l. Nature 1992, 355:551-555. Some evidence for short-range cell-cell interactions in sex detemlination in C elegan~ 10.

HI-TN~FERCP, WOOD WB: The tra-1 Gene Determines Sexual Phenotype Cell-autonomously in C. elegans. Cell 1990, 63:1193-1204.

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OW-S.SHORTRV, RENFREEMB, SHAWG: Primar}, Genetic Control of Somatic Sexual Differentiation in a Mammal. Nat,,re 1988, 331:716--717.

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PAhVERS J, BURGOYNE PS: In Situ Analysis of Fetal, Prepuberal and Adult XX-X%" Chimaeric Mouse Testes: Sertoli Ceils are Predominantly, but not Exclusively, XY. Develop men, 1991, 112:265-268. The hest e~idence yet that a few X'~"cells can give rise to Sertoli cells in the differentiating gonad, but that the majority do not - - however, the number of embryos examined w~assm;dL 23. ""

24. •

PATrK CE, KER~ JB, GOSDrN RG, JONES I~V, I IARD'," K, MUGGLETON-IIARRISA[., HANDYSIDE AH, \"{/HITTINGHAM D, HOOPEa ML: Sex Chimaerism, Fertility and Sex Determination in the Mouse. Development 1991, 113:311-325. A slightly confusing paper addressing the fonnation of XX Sertoli and X'Y follicle cells in XX ,---, XY chinlaeras. Their use of adt,h chimaeras means the rest, Its must be interpreted with caution. 25. "•

I~,'d2,tERS, BURGOYNE"PS: ~ Follicle Cells in the Ovaries of XO/X%"and XO/Xq'/Xq'Y Mosaic Mice. Development 1991, 111:1017-1020. This work demonstrates th:tt there is no disadvantage to an X'Y cell differentiating as a follicle cell. 26. 27. ••

P.ad~tERSJ, BUItGOYNEPS: The Mus musculus domesticus Tdy Allele Acts Later than the Mus musculus musculus Tdy Allele: A Basis for X"Y Sex Reversal in C57Bl/6-Ypos Mice. Development 1991, 113:709-714. This paper provides evidence that different alleles of SO' may act at slightly different times. 28.

FERGUSON~90gJ, JOANEN T: Temperature of Egg Incubation Determines Sex in Alligator mississippiensis. Natttre 1982, 296: 850-853.

ETCHEREM: Autosomal Genes Invoh,ed in Mammalian Primary Sex Determination. Philos 7)'ans R Soc Lond [Biol] 1988, 322:109-118.

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BURGO'~E PS: Role of Mammalian Y Chromosome in Sex Determination. Philos Trans R Soc Lond IBioll 1980, 322:63-72.

EICHEREM, \VA.';HBURN LL: Genetic Control of Primaty Sex Determination in Mice. Ann. Rev Genet 1986, 20:327-360.

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LOVELL-BArX3ER: The Role of Sty in Mammalian Sex Determination. In Posthnplantalion Development in the Mottse, Ciba Foundation 5),mposittm 165. Chichester, UK: Wiley & Sons Ltd; 1992:162-182.

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CAPEI.B, LOVELUBADGE R: The Sty Gene and Sex Determination in Mammals. In Advances in Det'elopmental Biologl' 1992, in press.

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CHABOTB, STEPHENSONDA, CHAPNU%NVM, BESMER P, BERNS'I'EIN A: The Proto-oncogene c-kit Encoding a Transmembrane Tyrosine Kinase Receptor Maps to the Mouse W Locus. Nature 1988, 335:88-89.

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ZSEBO KM, WIUaAMS DA, GEISSU:.It EN, BROUDY VC, IVlMtTtN FH, ATKINS HI., HSU R-Y, BIRKETr NC, OKINO KH, MtTRDOCK DC, ET AL: Stem Cell Factor is Encoded at the SI Locus of the Mouse and is the Ligand for the c-kit Tyrosine Kinase Receptor. Cell 1990, 63:213-224.

BUEHR M, McL-\RFN A: Mesonephric Contribution to Testis Differentiation in the Fetal Mouse. Development 1992, in press. An interesting study sugg,esting that a population of cells migrate into the genital ridge at a ktte stage and that these are required for proper testis difl;entiatk)n. 31.

18.

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McL,%RENA: Relating of Germ Ceil Sex to Gonadal Differentiation. In The Origin a n d Et,ohaion oJ Sex. Edited by Halvorsen HO, Monroy A. New York: Liss; 1985:289-300. MCLARE.N A: Chimeras

and

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BLANCHIME, FALCK)I.~ I., Fl:.Rlbxm S, LILLEY D/via: The DNAbinding Site of HMGI Protein is Composed of Two Similar Segments (HMG Boxes), Both of which have Coun. terparts in Other Eukatyotic Regulator}, Proteins. EMBO J 1992, 11:1055-1(/63. Describes some of the DNA-binding properties of LEF-I.

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NER SS: HMGs EvetTwhere. Cttrr Biol 1992, 2:208-210.

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VAN DE WETFRING M, OOS'FI'RWI-]GEI.l~'l, DOOIJES D, CLEVI:.RF,H: Identification and Cloning o f TCF-I, a T Lymphocyte-specific Transcription Factor Containing a Sequence-specific HMG Box. EMBO.I 1991, 10:123-132.

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in

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An elegant paper describing further details of the DNA-binding properties of LEF-1 and SRY proteins, in particular the demonstraUon that both induce a dramatic kink in the bound DNA. 41. WANGCC, NASH HA: T h e Interaction of E. coli IHF Protein with its Specific Binding Sites. Cell 1989, 57:869-880.

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NK':,RIN N, BUGGS G, KONG XF, CARNAZZA J, GOEBL M, AI.EXANDER-BRIDGESM: DNA-binding Properties of the Product of the Testis-determining Gene and a Related Protein. Nature 1991, 354:317-320.

MUNSTERBERGA, LOVELL-BADGER: Expression of the Mouse Anti-Miillerian Hormone Gene Suggests a Role in both Male and Femaie Sexual Differentiation. Development 1991, 113:613~24. A description of the cloning and expression of the mouse anti-Mtillerian hormone gene. 39. •"

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GIESE K, COX J, GROSSCHEDI. R: The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell 1992, 69:185-196.

R LovelI-Badge, Laboratot T of Molecular Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW'/ 1AA, UK.

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Testis determination: soft talk and kinky sex.

The activity of the Y-linked Sry gene during a critical period of gonadal differentiation is the normal trigger for testis determination and subsequen...
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