The Sonic Hedgehog (SHH) gene provides instructions for making a protein for animal development. The name was inspired by mutant fruit fly larvae covered in small, pointy denticles resembling a hedgehog. Researchers later identified three related genes in vertebrates, naming one after the video game character. The SHH gene directs the production of the Sonic Hedgehog protein, a chemical signal that orchestrates cell growth, specialization, and body shaping during embryonic development.
Function in Embryonic Development
During embryonic growth, the SHH protein acts as a morphogen. This signaling protein diffuses from a source and instructs developing cells what to become based on its concentration. The SHH protein creates a concentration gradient that provides spatial information to embryonic tissues, guiding their development.
The gene has a foundational role in patterning the early nervous system. It is secreted from the notochord and helps establish the floor plate of the neural tube, which becomes the spinal cord. This signaling is responsible for the top-to-bottom organization of the developing nervous system. Correct formation of the brain’s two hemispheres also depends on SHH signaling, which establishes the midline for the forebrain.
Beyond the central nervous system, SHH is instrumental in limb formation. The protein is secreted from a region in the developing limb bud known as the zone of polarizing activity. This signal organizes the limb’s structure, ensuring digits like fingers and toes form correctly. The gene’s influence also extends to facial development, where its signals are needed to form and separate the eyes.
The SHH Signaling Pathway
The SHH protein functions through a communication system called a signaling pathway. This process begins when a cell releases the SHH protein, which travels to other cells. The protein’s target is a receptor on the surface of a cell called Patched1 (PTCH1).
When the SHH protein is absent, the PTCH1 receptor represses another protein called Smoothened (SMO), keeping the pathway off. This inactivity leads to the processing of GLI proteins into a form that blocks the expression of target genes.
When SHH binds to the PTCH1 receptor, it stops PTCH1 from inhibiting SMO. This frees SMO to initiate a cascade of events inside the cell, preventing GLI proteins from being suppressed. The activated GLI proteins then move into the cell’s nucleus and turn on specific genes, altering the cell’s function and development.
Developmental Disorders Linked to the SHH Gene
Disruptions in the SHH gene or its signaling pathway during embryonic development can cause various developmental disorders. Mutations can produce a protein with reduced or no activity, impairing its patterning functions. These mutations are a primary cause of a condition known as Holoprosencephaly (HPE).
HPE is characterized by the failure of the developing forebrain to divide into two distinct hemispheres. The severity of HPE exists on a spectrum. In severe cases, the brain may not divide at all and can be accompanied by significant facial anomalies, including a single central eye (cyclopia). Milder forms may result in less severe brain and facial changes.
Mutations affecting the SHH pathway can also cause other structural anomalies like polydactyly, where an individual is born with extra fingers or toes. This occurs because the SHH signal that patterns the limbs is not correctly regulated. These conditions highlight the gene’s role in sculpting the embryonic form.
Role in Cancer and Adult Health
The SHH signaling pathway is most active during embryonic development and is largely silenced in most adult tissues. Improper reactivation of this pathway in adult cells can have serious consequences. Aberrant activation can drive the uncontrolled cell proliferation and growth characteristic of cancer.
Basal cell carcinoma, the most common form of skin cancer, is closely associated with abnormal SHH signaling. In many cases, mutations are found in the PTCH1 or SMO proteins. These mutations cause the pathway to become permanently switched on, leading to unchecked cell division.
Another cancer linked to the SHH pathway is medulloblastoma, a malignant brain tumor common in children. In a subgroup of these tumors, the cancer is driven by the constant activation of SHH signaling. Reactivation of this developmental pathway can transform normal adult stem cells into cancer stem cells that generate and sustain the tumor.
Medical and Therapeutic Applications
Understanding the SHH pathway’s role in cancer has led to the development of targeted therapies. Researchers created drugs, known as SHH pathway inhibitors, to block this pathway when improperly activated. These treatments interrupt the signaling cascade that drives tumor growth.
These inhibitor drugs work by targeting the SMO protein. By binding to SMO, they prevent it from sending growth signals downstream, even when the PTCH1 receptor is mutated. This approach shuts down the pathway below the initial mutation, halting cancer cell proliferation.
The SMO inhibitor vismodegib is approved for treating advanced basal cell carcinoma. This class of drugs is effective in shrinking tumors driven by SHH pathway activation. The development of these inhibitors is an active area of research, with studies exploring their use against other cancers.