Desert Hedgehog (Dhh) belongs to the highly conserved Hedgehog family of proteins which are involved in multiple developmental processes. Desert Hedgehog is a secreted, 45 kDa, 373 amino acid (aa) protein that undergoes autocatalytic cleavage between Gly198 and Cys199 catalyzed by the C-terminal domain, which releases the N-terminal domain with a concominant attachment of cholesterol at its new C-terminus. In addition to the C-terminally attached cholesterol, a fatty acid acyl chain is esterified to the N-terminal cysteine (aa 23) via an amide linkage. The 19 kDa N-terminal signaling domain is membrane associated due to its double lipid modifications. Its binding to Patched receptors results in the loss of Patched repression of Smoothened signaling [1-4]. Dhh binds both Patched and Patched 2 as well as Hedgehog interacting protein (Hip) [5]. Within the N-terminal domain human Dhh shares 97% aa sequence identity with mouse and rat Dhh. It shares approximately 75% aa seqeuence identity with human Indian (Ihh) and Sonic Hedgehog (Shh) [5]. Dhh is produced by Sertoli cells and is required for testis development and spermatogenesis [6, 7]. It induces steroidogenic factor 1, which is instrumental in promoting Leydig cell differentiation [8, 9]. It also promotes the deposition of basal lamina surrounding seminiferous tubules [6]. Mutations of Dhh are linked to complete pure gonadal dysgenesis [10]. Dhh is expressed in the female by ovarian granulosa cells and the corporus luteum [11]. Its upregulation in ovarian cancer correlates positively with proliferative index, and negatively with prognosis [12].
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