Desert Hedgehog (DHH) is a signaling protein that directs the development and organization of specific tissues. It belongs to a major family of signaling molecules that govern embryonic development. DHH transmits instructions between cells, guiding them into their proper roles and locations during the formation of organ systems. Its influence is pronounced in the development of the reproductive system and the peripheral nervous system. This article explores DHH’s biological context, its functions in normal development, and the health conditions that arise when its signaling is impaired.
Understanding the Hedgehog Signaling Family
DHH is one of three major mammalian proteins in the Hedgehog (Hh) family, named after the original gene discovered in fruit flies. The other two members are Sonic Hedgehog (SHH) and Indian Hedgehog (IHH). These proteins act as morphogens, meaning their concentration gradient across a tissue determines the identity and fate of local cells during embryonic pattern formation.
The signaling process begins when the DHH protein, or its family members, is secreted from a source cell and binds to the receptor protein Patched (PTCH) on the target cell surface. In the absence of DHH, PTCH inhibits the membrane protein Smoothened (SMO). When DHH binds to PTCH, this inhibition is released, allowing SMO to become active.
The activation of SMO triggers a cascade of events inside the cell that affects the GLI family of transcription factors. These factors move to the nucleus, where they regulate the expression of specific target genes. This molecular relay changes the receiving cell’s behavior, directing it to differentiate, proliferate, or organize into a complex structure.
DHH’s Critical Functions in Development
Male Sexual Differentiation
DHH plays a primary role in mammalian development, centering on male sexual differentiation. During embryonic development, DHH is first expressed by the pre-Sertoli cells in the developing testes. The signaling protein then acts on neighboring precursor cells, specifically the Leydig cells and the peritubular myoid cells.
This paracrine signaling induces Leydig cells to differentiate and produce testosterone, which is essential for forming male genitalia. DHH also regulates the differentiation of peritubular myoid cells. These cells organize with Sertoli cells to form the testis cords, the foundational structures of the seminiferous tubules. In the adult male, DHH expression continues in Sertoli cells, where it is required for maintaining spermatogenesis and fertility.
Peripheral Nervous System Maintenance
The second major role of DHH is the structural maintenance of the peripheral nervous system. DHH is secreted by Schwann cells, which are the glial cells responsible for insulating peripheral nerves. This signal directs surrounding mesenchymal cells to form the perineurial sheath, the connective tissue layer that encases the nerve bundle.
The perineurium is an extension of the blood-nerve barrier, functioning as a protective seal that isolates the nerve fibers. DHH signaling is required for the proper organization of this sheath and the formation of tight junctions. These junctions maintain the nerve’s internal environment. Disruption of this signaling can lead to structural defects in the nerve’s protective layers.
DHH Malfunction and Associated Disorders
Disruptions in the DHH gene lead to severe developmental conditions reflecting its dual functions. Mutations are a cause of 46,XY Disorders of Sex Development (DSD), specifically gonadal dysgenesis. Failure of the DHH signal prevents the proper differentiation of the embryonic testes.
The severity of the mutation determines the outcome. Complete loss of DHH function often results in 46,XY complete gonadal dysgenesis (CGD). Individuals with CGD have an XY chromosome complement but develop female external genitalia, an infantile uterus, and non-functional streak gonads instead of testes. Less severe mutations can lead to partial gonadal dysgenesis (PGD), resulting in ambiguous genitalia, undescended testes, or male infertility due to failed spermatogenesis.
DHH gene mutations that cause gonadal dysgenesis can also cause minifascicular polyneuropathy. This condition involves structural disorganization of the peripheral nerves, where the protective perineurial sheath is thin and defective. The name “minifascicular” refers to the abnormal formation of numerous small nerve bundles, or fascicles, within the nerve.
This structural defect compromises the blood-nerve barrier, leading to functional problems like reduced nerve conduction velocity and demyelination. The co-occurrence of gonadal dysgenesis and minifascicular neuropathy demonstrates the protein’s simultaneous roles in the reproductive and nervous systems. This dual pathology highlights how a single signaling failure can lead to complex, multisystemic disorders.