Sox9 and Sox8 are required for basal lamina integrity of testis cords and for suppression of FOXL2 during embryonic testis development in mice

TY - JOUR

T1 - Sox9 and Sox8 are required for basal lamina integrity of testis cords and for suppression of FOXL2 during embryonic testis development in mice

AU - Georg, Ina

AU - Barrionuevo, Francisco

AU - Wiech, Thorsten

AU - Scherer, Gerd

PY - 2012/10/1

Y1 - 2012/10/1

N2 - The sex-determining gene Sry and its target gene Sox9 initiate the early steps of testis development in mammals. Of the related Sox genes Sox8, Sox9, and Sox10, all expressed during Sertoli cell differentiation, only inactivation of Sox9 before the sex determination stage at Embryonic Day 11.5 (E11.5) causes XY sex reversal, while Sox9 inactivation after this stage has no effect on testis cord differentiation. We have previously shown that both Sox9 and Sox8 are essential for maintaining testicular function in post-E14.0 Sertoli cells. To gain insight into the molecular and cellular processes underlying the abnormal development of Sox9 and Sox8 mutant testes, we performed a detailed developmental study of embryonic and neonatal stages. We observe a progressive disruption of the basal lamina surrounding the testis cords that starts at E17.5 and already at E15.5 reduced expression levels of collagen IV, collagen IXa3 and testatin, structural components of the basal lamina, and the extracellular matrix transcriptional regulator Scleraxis. Lineage tracing reveals that mutant Sertoli cells delaminate from testis cords and are present as isolated cells between remaining cords. Also, Sox10 expression is strongly reduced in the absence of Sox9 and/or Sox8. Finally, we document increasing expression of the ovarian marker FOXL2 in mutant cords starting at E15.5, indicating progressive transdifferentiation of mutant Sertoli cells. This study shows that Sox9 and Sox8 maintain integrity of the basal lamina to prevent testis cord disintegration and that both factors actively suppress the ovarian program during early testis development.

AB - The sex-determining gene Sry and its target gene Sox9 initiate the early steps of testis development in mammals. Of the related Sox genes Sox8, Sox9, and Sox10, all expressed during Sertoli cell differentiation, only inactivation of Sox9 before the sex determination stage at Embryonic Day 11.5 (E11.5) causes XY sex reversal, while Sox9 inactivation after this stage has no effect on testis cord differentiation. We have previously shown that both Sox9 and Sox8 are essential for maintaining testicular function in post-E14.0 Sertoli cells. To gain insight into the molecular and cellular processes underlying the abnormal development of Sox9 and Sox8 mutant testes, we performed a detailed developmental study of embryonic and neonatal stages. We observe a progressive disruption of the basal lamina surrounding the testis cords that starts at E17.5 and already at E15.5 reduced expression levels of collagen IV, collagen IXa3 and testatin, structural components of the basal lamina, and the extracellular matrix transcriptional regulator Scleraxis. Lineage tracing reveals that mutant Sertoli cells delaminate from testis cords and are present as isolated cells between remaining cords. Also, Sox10 expression is strongly reduced in the absence of Sox9 and/or Sox8. Finally, we document increasing expression of the ovarian marker FOXL2 in mutant cords starting at E15.5, indicating progressive transdifferentiation of mutant Sertoli cells. This study shows that Sox9 and Sox8 maintain integrity of the basal lamina to prevent testis cord disintegration and that both factors actively suppress the ovarian program during early testis development.

KW - Animals

KW - Basement Membrane

KW - Cell Membrane Permeability

KW - Cell Transdifferentiation

KW - Female

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation, Developmental

KW - Gene Silencing

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Pregnancy

KW - SOX9 Transcription Factor

KW - SOXE Transcription Factors

KW - Sertoli Cells

KW - Testis

U2 - 10.1095/biolreprod.112.101907

DO - 10.1095/biolreprod.112.101907

M3 - SCORING: Journal article

C2 - 22837482

VL - 87

SP - 99

JO - BIOL REPROD

JF - BIOL REPROD

SN - 0006-3363

IS - 4

ER -