Desert Hedgehog (DHH) is a communication molecule that orchestrates the development of specific tissues during embryonic and adult life. This protein belongs to a fundamental group of biological messengers that tell cells how to grow, differentiate, and organize themselves into complex structures. Its function is tightly controlled, ensuring cells receive the right instructions for the proper formation and maintenance of organs and nerves.
Defining Desert Hedgehog (DHH)
DHH is a protein encoded by the DHH gene in humans and serves as a signaling molecule. It is a member of the conserved Hedgehog (Hh) family of proteins, which also includes Sonic Hedgehog (SHH) and Indian Hedgehog (IHH). These proteins regulate morphogenesis, the biological process that causes an organism to develop its shape. In mammals, the three forms have distinct but occasionally overlapping roles in guiding development.
DHH is initially produced as a precursor that undergoes autocatalytic cleavage. This self-processing splits the protein into a signaling fragment and a C-terminal fragment, attaching a cholesterol molecule to the active signaling portion.
This lipid modification anchors the DHH signal to the cell surface, restricting its movement. This allows DHH to act primarily on neighboring cells in a localized, cell-to-cell communication manner, crucial for precise tissue patterning.
Essential Roles in Tissue Development
DHH plays a highly focused role in the development and maintenance of two distinct systems: the reproductive organs and the peripheral nervous system. Its functions are particularly important in male reproductive development, but they extend to both sexes and the nervous system.
Reproductive Development
In the developing male, DHH is expressed by Sertoli cells within the testes. It acts on surrounding cells, specifically directing precursor cells to differentiate into Leydig cells, which produce androgens like testosterone. This signaling is necessary for normal testicular differentiation and the later stages of sperm production, known as spermatogenesis.
In the female reproductive system, DHH and IHH are expressed by granulosa cells and act together in the ovaries. Their signaling is required for the development of theca cells, which surround the ovarian follicles. Theca cells are essential for producing the hormones necessary for ovulation, meaning DHH guides the formation of necessary supporting cell types in both males and females.
Nervous System
DHH is also involved in the formation of peripheral nerves, which transmit signals between the central nervous system and the rest of the body. It is expressed by Schwann cells, the glial cells that wrap around nerve axons to form the protective myelin sheath. DHH signaling is required for the proper development of the perineurium, the specialized connective tissue membrane that encases bundles of nerve fibers. This ensures the structural integrity and proper insulation of the peripheral nerves, necessary for efficient signal transmission.
How the DHH Signaling Pathway Works
The DHH signaling pathway is a cascade that converts the external protein signal into a change in gene expression inside a receiving cell. This process relies on components situated primarily on the cell surface and within the primary cilium.
The process begins when DHH binds to its receptor, Patched (PTCH). In the absence of DHH, PTCH inhibits the activity of Smoothened (SMO), a signal transducer, keeping the pathway silent by preventing SMO from accumulating in the primary cilium. When DHH binds to PTCH, it releases this inhibition.
SMO then translocates into the primary cilium, initiating the downstream signaling cascade. This activation leads to the stabilization and release of transcription factors known as GLI proteins (GLI1, GLI2, and GLI3). Before SMO activation, GLI factors are held inactive by Suppressor of Fused (SUFU). SMO activation causes the dissociation of the GLI-SUFU complex, allowing active GLI proteins to enter the cell nucleus. Once inside, GLI proteins bind to specific DNA sequences to change the transcription rate of target genes, altering the cell’s behavior.
Consequences of DHH Pathway Disruption
Malfunction of the DHH signaling pathway, often due to genetic mutations in the DHH gene, can lead to specific developmental disorders related to its functions in the gonads and nerves. One recognized consequence is a disorder of sex development in individuals with a male (46,XY) chromosome pattern.
Mutations in DHH can prevent the proper formation of testes, a condition known as gonadal dysgenesis. This results in the individual developing female-typical external characteristics and internal structures, such as a uterus and fallopian tubes. The disruption can also manifest as male infertility due to a lack of mature sperm production and poorly developed testicular structures.
The second major outcome is peripheral neuropathies, nerve abnormalities affecting the peripheral nervous system. Because DHH is necessary for proper nerve sheath formation by Schwann cells, its loss can lead to weakness and loss of sensation in the extremities. The combination of gonadal dysgenesis and peripheral neuropathy is a specific clinical condition linked to DHH gene variants, underscoring the protein’s dual role.