The Desert Hedgehog Signalling Pathway in Human Gonadal Development and Differences of Sex Development

Abstract

While the Hedgehog signalling pathway is implicated in numerous developmental processes and maladies, variants in the <i>Desert Hedgehog</i> (<i>DHH</i>) ligand underlie a condition characterised by 46,XY gonadal dysgenesis with or without peripheral neuropathy. We discuss here the role and regulation of <i>DHH</i> and its signalling pathway in the developing gonads and examine the current understanding of how disruption to this pathway causes this difference of sex development (DSD) in humans.

Export of polybasic motif–containing secretory proteins BMP8A and SFRP1 from the endoplasmic reticulum is regulated by surfeit locus protein 4

“…To test whether SURF4 plays a general role in regulating ER export of these polybasic motif–containing secretory proteins, we analyzed the ER export of four secretory proteins in the list (Dhh, Ihh, BMP8A, and SFRP1). Dhh and Ihh are members of the Hh family, and they function in testis organogenesis and chondrocytes, respectively ( 20 , 21 ). BMP8A plays a role in calcium regulation and bone homeostasis ( 22 ).…”

Deciphering Sex-Specific Differentiation of Human Fetal Gonads: Insight From Experimental Models

“…DHH is secreted by Sertoli cells, while the receptors PTCH1 and PTCH2 mediating the effects of DHH are expressed in Leydig cell precursors based on single cell RNA sequencing data from ( Li et al, 2017 ) viewed in the ReproGenomicsViewer ( Darde et al, 2019 ). Loss of function mutations in DHH is associated with 46,XY DSD ranging from partial to complete gonadal dysgenesis with the presence of Müllerian structures ( Rothacker et al, 2018 ; Pachernegg et al, 2021 ). Conversely, mutations in the PDGF system has not been associated with DSD but instead found in various cancers and fibrotic diseases ( Guérit et al, 2021 ).…”

From mesenchymal niches to engineered in vitro model systems: Exploring and exploiting biomechanical regulation of vertebrate hedgehog signalling

“… [ 33 ] Desert hedgehog (DHH) Expressed in male testis, skin, and controls the formation of the peripheral nerve sheath. [ 34 ] Receptors Patched1 (PTCH1) Interacts and binds to the Hh proteins to initiate pathway activation. [ 35 ] Patched2 (PTCH2) •Poorly characterised and dispensable in embryogenesis.…”