CELSR1

CELSR1, also known as Cadherin EGF LAG seven-pass G-type receptor 1, is a gene that encodes a large atypical cadherin transmembrane protein belonging to the Flamingo subfamily of adhesion G protein-coupled receptors (aGPCRs). In humans, the CELSR1 gene is located on chromosome 22q13.31.

CELSR1 proteins are characterized by a large extracellular domain containing multiple cadherin, epidermal growth factor (EGF)-like, and laminin-G-like (LAG) repeats, followed by a seven-transmembrane spanning domain (7TM) and a cytoplasmic tail. They are involved in cell-cell adhesion, planar cell polarity (PCP), and tissue morphogenesis during development.

Function

CELSR1 plays a critical role in establishing and maintaining planar cell polarity, which is the coordinated orientation of cells within the plane of an epithelium. This process is essential for the proper development of numerous tissues and organs, including the neural tube, inner ear, and skin. CELSR1 interacts with other core PCP proteins, such as Vangl1/2, Frizzled (Fzd), and Dishevelled (Dsh), to regulate cytoskeletal organization and cell shape changes.

Beyond PCP, CELSR1 also contributes to cell migration, axonal guidance, and synapse formation. Its involvement in these diverse processes highlights its importance in neural development and function.

Clinical Significance

Mutations in the CELSR1 gene have been associated with several human diseases and developmental disorders. These include:

• Neural Tube Defects (NTDs): CELSR1 is implicated in the closure of the neural tube during embryonic development, and mutations can increase the risk of NTDs, such as spina bifida and anencephaly.
• Auditory Dysfunction: CELSR1 is crucial for the proper development of the inner ear. Mutations can disrupt the organization of hair cells and lead to hearing loss.
• Neurodevelopmental Disorders: Studies suggest a potential link between CELSR1 variants and neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability. Further research is needed to fully understand these associations.
• Cancer: Altered expression of CELSR1 has been observed in various cancers, potentially impacting cell proliferation, migration, and metastasis. Its role in cancer is complex and may vary depending on the specific tumor type.

Structure

The CELSR1 protein is composed of a large extracellular domain containing approximately nine cadherin domains, eight EGF-like repeats, and three laminin-G-like domains. The seven transmembrane helices form a characteristic aGPCR structure. The intracellular C-terminal tail contains potential phosphorylation sites, suggesting regulation by intracellular signaling pathways.

Interactions

CELSR1 interacts with a variety of other proteins, including:

• Vangl1 and Vangl2: Core PCP proteins essential for planar cell polarity.
• Frizzled (Fzd) receptors: Wnt receptors that play a central role in PCP signaling.
• Dishevelled (Dsh) proteins: Cytoplasmic phosphoproteins that mediate Wnt/PCP signaling.
• Fat and Dachsous (Ft/Ds) cadherins: Large atypical cadherins that contribute to PCP establishment.

Research

CELSR1 remains an active area of research. Scientists are working to further elucidate its precise roles in development, disease, and signaling pathways. Studies using model organisms, such as mice and zebrafish, are providing valuable insights into the function and regulation of CELSR1. Understanding CELSR1's complex mechanisms may lead to the development of novel therapies for related diseases.