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First published online 13 April 2005
doi: 10.1242/dev.01826

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Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development

¹ Division of Endocrinology and Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
² Division of Endocrinology and Medicine and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA

View larger version (72K): [in a new window]   Fig. 1. Expression of fetal Leydig cell markers in embryonic testes of single and double Sf1 and Dax1 mutants. In situ hybridization for steroidogenic enzymes Cyp17 (A-D) and Cyp11a1 (E-H) identifies the Leydig cells of the embryonic testis at 13.5 dpc. Leydig cells are present in columns between testis cords in wild-type mice (A,E). Leydig cells are decreased in Sf1+/– gonads in agreement with dosage-sensitive regulation (B,F), and are restricted to the coelomic surface of the Dax1-/Y testis (C,G). Sf1/Dax1 double mutant mice are devoid of Leydig cells markers (D,H).

View larger version (120K): [in a new window]   Fig. 2. Desert hedgehog expression in embryonic testes of single and double Sf1 and Dax1 mutants. In situ hybridization of the Sertoli marker Dhh is shown at E11.5 (A-D) and E12.5 (E-H) in genital ridges. The coelomic surface is at the top; anterior is to the left. At E11.5, both Sf1+/– and Dax1-/Y single mutants expressed reduced amounts of Dhh (B,C). Expression of Dhh is undetectable in the gonad of the double mutant (D). By E12.5, Dhh expression is comparable in wild-type and single mutant gonads (E-G), and is restored in the double mutant (H). (I-L) Lack of apoptotic death in cells of the E11.5 gonad by TUNEL staining (green) of lateral sections, compared with the Sf1 knock out shown in the inset in I. Arrowhead indicates the coelomic epithelial surface.

View larger version (78K): [in a new window]   Fig. 3. Amh expression in embryonic testes of single and double Sf1 and Dax1 mutants. Amh expression is localized to the primitive gonadal ridge in the wild-type male at E11.5 (A). Sf1 heterozygous gonads show early loss of Amh expression (B), but recover by E12.5 (F). Dax1 null mutant gonads also have markedly reduced Amh expression (C), followed by immediate recovery at E12.5 (G). The recovery of Amh expression is further delayed in the double mutants when compared with the single mutants (D,H).

View larger version (80K): [in a new window]   Fig. 4. Sox9 expression in embryonic testes of single and double Sf1 and Dax1 mutants. In situ hybridization for Sox9 was performed at 11.5 dpc (A-D) and at 12.5 dpc (E-H). Sox9 expression is detected in the wild-type male gonad during the bipotential stage at E11.5 (A). Sox9 expression in Sertoli cells is diminished in the Sf1 heterozygous mutant, the Dax1 null mutant and the double mutant (B-D), when compared with wild type. At 12.5 dpc, normal testis cord organization and the presence of Sertoli cells is indicated by Sox9 expression in both wild-type and Sf1+/– gonads (E,F). Although Sertoli cells are present, testis cords are not easily identifiable in either the Dax1-/Y gonad or the Sf1/Dax1 double mutant gonad (G,H).

View larger version (76K): [in a new window]   Fig. 5. Testis cord morphogenesis in Sf1 and Dax1 mutant male gonads. Testis differentiation is characterized by morphogenesis of primitive testis cords in tissue stained by Hematoxylin and Eosin. Cross-sectional histology of wild-type gonad tissue shows round cord structures containing Sertoli and germ cells enclosed by flattened peritublar myoid cells (A). Sf1 heterozygous gonads retain cord morphology (B). Dax1 null (C) and Sf1/Dax1 double mutant (D) gonad tissue both show a more disorganized patterning, reflecting Dax1 deficiency in both cases.

View larger version (116K): [in a new window]   Fig. 6. Leydig cell development recovers by neonatal age. Consistent with Dhh recovery, low levels of Cyp17 and Cyp11a1 expression are detectable as early as E14.5. Expression of Cyp17 (A-D) and Cyp11a1 (E-H) recover by E14.5. Recovery of fetal Leydig cell differentiation was assessed by analysing 3ßHSD protein levels at 2 weeks after birth, prior to the proliferation of adult Leydig cells. Two-week-old testis stained for 3ßHSD (I-L) confirms the presence of Leydig cells. Therefore, prior to the proliferation of adult Leydig cells, fetal Leydig cell differentiation is complete.