Extracellular matrix-associated proteins in fetal gonad and reproductive tract development.

摘要

Similar to all organs, growth factor and morphogen signaling is critical for gonad differentiation. However, gonad development is unique because testes and ovaries develop from a common bipotential progenitor. These facts suggest that gonad development is likely to employ sex-specific responses to, or expression of, certain growth factors and morphogens. Evidence suggests that extracellular matrix (ECM) associated proteins such as heparan sulfate proteoglycans (HSPGs) and matricellular proteins can influence how growth factors and morphogens diffuse and/or interact with their receptors, thereby modulating downstream signaling events. I hypothesize that some of these ECM-associated proteins may modulate sex-specific responses to growth factors and/or morphogens.;To determine possible roles for ECM-associated proteins in mediating growth factor/morphogen signaling in developing gonads, the expression and regulation of HSPGs and their modifying enzymes, as well as two genes encoding matricellular proteins, Smoc1 and Smoc2, were assessed in fetal mouse gonad/mesonephros complexes. This analysis showed that specifically modified HSPGs and two classes of modifying enzymes, 6- O-sulfotransferases and sulfatases, are expressed in sexually dimorphic patterns during fetal gonad development. Analysis of mice deficient in the heparan sulfate 6-O-sulfotransferase 1 modifying enzyme suggested that this gene is necessary for normal Leydig cell development. Overall these data suggest that specifically modified HSPGs mediate growth factor/morphogen signaling during gonad development.;My analysis of Smoc1 and Smoc2 suggested that they have important roles in gonad and mesonephros development. Smoc1 was expressed in testicular pre-Sertoli and ovarian pre-granulosa cells and was reduced in mutants with early gonad development defects. After E12.5 Smoc1 expression was downregulated in ovaries, but persisted in testes indicating a sexually dimorphic role in supporting cell progenitor development. Smoc2 was expressed in testicular Leydig cells and in the urogenital ducts of both sexes. Smoc2 expression was found to depend on Hedgehog signaling in the testis, mesonephros, and kidney. Additionally, Smoc2 was expressed in ectopic adrenal cells in Wnt4 mutant ovaries and in the adrenal cortex. Overall these data suggest cell-type specific roles for Smoc1 and Smoc2 in mediating intercellular signaling during gonad development, specifically in supporting cell progenitors, steroidogenic cells, and in the reproductive tract.