The Sonic the Hedgehog gene, often referred to as SHH, is a crucial gene in the intricate process of organism development. It orchestrates the formation of various body structures from the earliest embryonic stages, ensuring proper formation.
The Origin of an Unforgettable Name
The gene’s name originated from research on fruit flies, Drosophila melanogaster. In 1980, Christiane Nüsslein-Volhard and Eric Wieschaus, who later shared a Nobel Prize, identified a gene they named “hedgehog.” They chose this name because when mutated, the fly larvae developed spiky projections on their exoskeletons, resembling a hedgehog’s spines.
As scientists began to discover related genes in vertebrates, the tradition of quirky naming continued. Robert Riddle, a postdoctoral fellow in Cliff Tabin’s lab, named one of these newly discovered genes “Sonic hedgehog.” The inspiration came from a magazine advertisement for Sega’s popular video game character, Sonic the Hedgehog, brought home by his wife. Other related genes were named “Desert hedgehog” and “Indian hedgehog,” but Sonic hedgehog gained prominence due to its widespread functions.
Function in Embryonic Development
The Sonic hedgehog (SHH) protein acts as a “morphogen,” a signaling molecule that guides cell differentiation and patterning based on its concentration. Like a radio signal, cells closer to the transmitter receive a stronger signal and respond differently than those farther away, leading to distinct developmental outcomes. This concentration gradient allows SHH to provide positional information across developing tissues.
A primary role of SHH is in neural tube patterning, which forms the brain and spinal cord. SHH, secreted by the notochord and floor plate at the midline, establishes the ventral (bottom) half of the neural tube. This signaling gradient helps separate the brain into two hemispheres and ensures proper eye placement.
SHH also plays a significant role in limb development, particularly in patterning the digits. It is expressed in a specific region at the posterior margin of the limb bud called the Zone of Polarizing Activity (ZPA). The SHH signal from the ZPA creates a gradient that instructs cells on their identity, ensuring fingers and toes form in their correct positions and numbers along the limb’s anterior-posterior axis.
Consequences of Genetic Mutations
When the functions of the Sonic hedgehog gene are disrupted during embryonic development, it can lead to various congenital disorders. A prominent example is Holoprosencephaly (HPE), a birth defect characterized by the incomplete separation of the forebrain into left and right hemispheres. Mutations in the SHH gene are a common cause of both sporadic and inherited forms of HPE.
The severity of HPE can vary widely, ranging across a spectrum of phenotypes. Milder forms might present with closely spaced eyes (hypotelorism) or a single central incisor. In its most severe presentation, HPE can result in cyclopia, where the brain fails to divide, leading to a single eye and often a proboscis-like nasal structure. This condition is incompatible with life after birth.
Disruptions in SHH signaling can also manifest as limb abnormalities. For instance, an overactive SHH signal or its ectopic expression in the anterior limb bud can lead to polydactyly, or extra fingers or toes. This occurs when patterning instructions are misinterpreted.
Role in Adult Health and Disease
While its role in embryonic development is well-known, the Sonic hedgehog pathway remains active, albeit at lower levels, in adult organisms. It contributes to the maintenance of adult stem cells, which replenish tissues and facilitate regeneration. For example, SHH signaling is involved in hair follicle renewal and may play a role in bone regeneration following injury.
The inappropriate reactivation or dysregulation of the SHH signaling pathway in adults is linked to the development of certain cancers. When the pathway is abnormally active, it can promote uncontrolled cell growth and proliferation. This aberrant signaling is often mutation-driven in specific tumor types.
Two notable examples of cancers associated with SHH pathway dysregulation are basal-cell carcinoma (BCC) and medulloblastoma. Basal-cell carcinoma, the most common form of skin cancer, frequently arises from mutations that activate the SHH pathway. Medulloblastoma, a malignant brain tumor primarily affecting children, also exhibits activated SHH signaling due to mutations within the pathway.