Prospero-related homeobox 1, or Prox1, is a protein that acts as a transcription factor. Prox1 controls which genes are turned on or off within cells, a process necessary for proper cell development and function throughout the body. This regulation influences various biological processes, ensuring cells develop into their correct types and perform their specialized tasks.
Prox1 and the Lymphatic System
Prox1 is primarily known for its role in the development and maintenance of the lymphatic system. This system, a network of vessels, collects fluid, proteins, and immune cells from tissues and returns them to the bloodstream. It also plays a role in immune function by transporting immune cells to lymphoid organs.
During embryonic development, Prox1 is expressed in endothelial cells in the cardinal veins. These Prox1-expressing cells then bud and sprout from the veins to form the initial lymphatic vessels. Prox1 is considered a master regulator of lymphatic endothelial cell (LEC) specification and sprouting.
Without functional Prox1, the budding and sprouting of these cells are arrested, leading to embryos that lack lymphatic vasculature. The cells that would normally become lymphatic vessels instead maintain characteristics of blood vessel endothelial cells. This indicates Prox1 is required for both lymphatic vessel formation and the differentiation of endothelial cells into their lymphatic identity.
Dysfunction of Prox1 in the lymphatic system can lead to lymphedema, a condition characterized by chronic limb swelling due to insufficient fluid drainage. Research has explored therapeutic approaches for lymphedema by using gene delivery of Prox1 to promote lymphangiogenesis, the formation of new lymphatic vessels. Overexpression of Prox1 can induce cells to differentiate into lymphatic endothelial-like cells, which may offer a cell transplantation therapy.
Prox1’s Diverse Roles in Body Development
Beyond its important role in the lymphatic system, Prox1 has diverse functions in the development and maintenance of various other organs and tissues. In the eye, Prox1 is important for lens development, specifically for the elongation of lens fiber cells. Without Prox1 activity, lens cells fail to elongate and differentiate, resulting in an abnormal, hollow lens structure.
In the liver, Prox1 helps maintain hepatocyte identity, the main functional cells of the liver. It represses genes that would alter hepatocyte identity, safeguarding their specialized function. Prox1 also contributes to liver regeneration after injury.
Prox1 is also involved in the development of the pancreas, influencing its structure and specific cell type formation. It plays a role in the production of pancreatic islet cells, responsible for hormone production, such as insulin. The absence of Prox1 can lead to premature differentiation of exocrine cells and affect the branching of epithelial structures within the developing pancreas.
In the brain, Prox1 is expressed in the dentate gyrus, a hippocampus region important for learning and memory. It is necessary for granule cell maturation during development and for maintaining intermediate progenitors during adult neurogenesis. Prox1 also influences neuronal migration and differentiation, promoting early neuronal identity. In the intestine, Prox1-positive cells act as sensors for the cholinergic niche, contributing to the differentiation and expansion of enteroendocrine tuft cells involved in maintaining intestinal homeostasis.
Prox1’s Link to Disease
Dysregulation of Prox1 has been linked to various cancers and metabolic disorders. Its role in cancer is complex, as it can act as both a tumor suppressor and an oncogene, depending on the cancer type and context. This dual nature highlights the molecular pathways Prox1 influences.
In colorectal cancer (CRC), Prox1 often promotes tumor progression. High Prox1 expression in CRC is associated with poor prognosis and can enhance the expansion of colorectal cancer stem cells, fueling tumor growth and resistance to low oxygen conditions. Prox1 is also a direct target of the Wnt/β-catenin signaling pathway, frequently altered in colorectal tumorigenesis.
Conversely, in hepatocellular carcinoma (HCC), the most common type of liver cancer, Prox1’s role appears contradictory across studies. Some research indicates that high Prox1 expression in primary HCC tissues correlates with worse survival and early tumor recurrence, suggesting an oncogenic role. Other studies have reported that loss of Prox1 in HCC patients is associated with a better prognosis, and that Prox1 can inhibit the proliferation of HCC cells, implying a tumor-suppressive function.
Beyond cancer, Prox1 has potential connections to metabolic disorders such as obesity and type 2 diabetes. Genetic variants in the PROX1 gene have been associated with altered glucose and lipid metabolism. For instance, certain PROX1 genotypes have been linked to higher visceral fat accumulation and differences in glucose utilization after meals. These findings suggest that Prox1 variants may have broad effects on metabolic pathways, making it a subject of ongoing research for understanding and preventing these conditions.