Sertoli cell signaling by Desert hedgehog regulates the male germline

BACKGROUND In mammals, testis development is initiated in the embryo in response to the expression of the sex determining gene, Sry, in Sertoli cell precursors. Subsequently, Sertoli cells are thought to play a central role in male-specific cell interactions, including those that occur during spermatogenesis. However, the molecular nature of these interactions is poorly understood. Desert hedgehog (Dhh) encodes a signaling molecule expressed in the testis, but not the ovary, and may therefore play a role in the regulation of spermatogenesis. RESULTS Dhh expression is initiated in Sertoli cell precursors shortly after the activation of Sry and persists in the testis into the adult. Female mice homozygous for a Dhh-null mutation show no obvious phenotype, whereas males are viable but infertile, owing to a complete absence of mature sperm. Examination of the developing testis in different genetic backgrounds suggests that Dhh regulates both early and late stages of spermatogenesis. Patched, a likely target of Hedgehog signaling, also displays male-specific transcription in the gonad. This expression is restricted to a second somatic lineage, the Leydig cells. The expression of Patched is lost in Dhh mutants. CONCLUSIONS Dhh expression in pre-Sertoli cells is one of the earliest indications of male sexual differentiation. Analysis of a null mutant demonstrates that Dhh signaling plays an essential role in the regulation of mammalian spermatogenesis. Loss of Patched expression in Dhh mutants suggests a conservation in the Hedgehog signaling pathway between flies and mice, and indicates that Leydig cells may be the direct target of Dhh signaling.