SUN-086 Role Of Ciliopathy Gene, Cc2d2a, In Pituitary Gland Development In Mice

Abstract Disclosure: S. Guha: None. S.W. Athul: None. B.S. Ellsworth: None. Ciliopathies refer to genetic disorders that affect different systems of the human body which are caused by mutations in unrelated genes ultimately affecting ciliary structure and/or function. Cilia have a ubiquitous presence in cellular organisms and therefore aberrant ciliogenesis has pleiotropic effects. Primary cilia are major sensory organelles acting as the sites of some of the most developmentally significant signal transduction pathways such as Shh, Wnt and BMP signaling. Because of the developmental role of primary cilia, ciliopathies result in a multitude of disease phenotypes such as neural tube defects, cognitive defects, polycystic kidneys, retinal degradation and obesity. They can also cause multi-system defects such as Bardet-Biedl Syndrome (BBS), Joubert Syndrome (JBTS) and Meckel Syndrome (MKS). Mutations in the ciliopathy gene, Cc2d2a, have been linked to JBTS-9 and MKS-6 and the protein CC2D2A is implicated in organogenesis. Here we explore the role of CC2D2A in pituitary gland development in mice. To that end we used C57BL/6J mice containing an ENU-induced mutation in the Cc2d2a gene, which converts a cytosine to thymine at position 2845 of the cDNA rendering the protein inactive. Mice were bred to homozygosity to generate Cc2d2a null embryos. We examined E14.5 wild type, heterozygous and null embryos for Cc2d2a and discovered variable pituitary phenotypes, ranging from hypoplastic and malformed pituitary to complete absence of discernible pituitary tissue in the Cc2d2a null counterparts. We also looked at the expression of critical transcription factors playing a role in pituitary gland development such as early markers like PITX2 and late markers like POU1F1 through immunohistological studies and discovered that pituitary cell differentiation is markedly affected in the Cc2d2a null embryos. This was also evident from the reduced to no expression of pituitary hormones such as ACTH and TSHB in the same Cc2d2a null embryos. These results interestingly highlight a novel role of CC2D2A in pituitary organogenesis and development and provide further insights into potential endocrinological manifestations that may occur in ciliopathies. Presentation: Sunday, July 13, 2025