The DCC gene, short for “Deleted in Colorectal Carcinoma,” was identified in 1990 during studies of colorectal tumors. Researchers isolated the gene from a segment of chromosome 18q that was frequently missing in cancer cells. Its absence in these cells suggested it played a role in suppressing cancer, sparking research in both cancer biology and developmental neuroscience.
The DCC Gene’s Blueprint: Normal Functions
The DCC gene provides instructions for producing a protein that acts as a transmembrane receptor, sitting across the cell’s outer membrane. This protein has a large extracellular portion that binds to other molecules, a segment crossing the membrane, and an internal tail that transmits signals into the cell. This structure allows it to receive signals from outside and trigger specific cellular responses.
One of the primary functions of the DCC protein is to act as a receptor for a molecule called netrin-1. When netrin-1 binds to the DCC receptor, it initiates a cascade of signals inside the cell that guides processes like cell migration. This movement of cells is fundamental during development and for tissue maintenance.
Beyond its interaction with netrin-1, the DCC protein is involved in cell adhesion, helping cells stick to one another and to the surrounding extracellular matrix. The protein also plays a role in programmed cell death, or apoptosis. In the absence of its ligand, netrin-1, the DCC receptor can initiate a signaling pathway that leads to the cell’s self-destruction.
DCC’s Role in Cancer Suppression
The DCC gene is classified as a tumor suppressor because it helps control cell growth, primarily through its ability to induce apoptosis. Loss of DCC function is a frequent event in colorectal cancer progression. A genetic event called loss of heterozygosity (LOH) is common at the gene’s chromosomal location, occurring in about 70% of these cancers. LOH means one gene copy is lost; if the other copy is inactivated, the cell loses DCC function and can evade apoptosis to spread.
While named for its link to colorectal cancer, suppressed DCC expression is also implicated in other malignancies, including gastric cancer, esophageal carcinoma, and some brain tumors. This often involves epigenetic silencing, where the gene is turned off by chemical modifications rather than deleted. The loss of DCC is associated with more advanced stages of cancer, suggesting its role is in tumor progression rather than initial formation.
DCC and Guiding Neural Pathways
The DCC gene is also integral to the development of the nervous system through a process known as axon guidance. This process ensures that nerve cells, or neurons, form correct connections by extending long projections called axons. These axons must navigate complex environments to reach their precise targets, forming the brain’s intricate wiring.
On a growing axon, the DCC receptor responds to environmental signals, most notably netrin-1. Netrin-1 acts as a chemoattractant, creating a chemical trail for the axon to follow. The binding of netrin-1 to DCC on the axon’s growth cone triggers signaling that directs growth toward the netrin-1 source.
This interaction guides commissural axons, which are nerve fibers that cross the midline of the central nervous system to connect its two sides. The DCC receptor steers these axons toward the midline where netrin-1 is concentrated. Proper DCC function is necessary for establishing circuitry for communication between different parts of the nervous system.
Impact of DCC Gene Changes on Health
Hereditary alterations in the DCC gene, known as germline mutations, can disrupt neural development and cause a spectrum of neurological disorders. These conditions are present in every cell of the body and are not related to cancer. They highlight the gene’s role in establishing the architecture of the central nervous system.
One well-documented condition is Congenital Mirror Movements (CMM), a rare disorder where intentional movements on one side of the body are involuntarily mirrored by identical movements on the opposite side. This condition is caused by abnormal organization of the corticospinal tracts, the major nerve pathways controlling voluntary movement. Mutations in DCC disrupt the normal crossing of these nerve fibers at the midline of the nervous system.
A mutation in one copy of the DCC gene (monoallelic) can cause CMM and is sometimes associated with agenesis of the corpus callosum, where the nerve bundle connecting the brain hemispheres is partially or completely absent. More severe mutations affecting both copies (biallelic) can lead to developmental split-brain syndrome. These disorders show the direct link between DCC’s integrity and the nervous system’s wiring.