SAT-029 MKS1 and its potential role in pituitary gland development

Abstract Disclosure: N. Mojahed: None. S.W. Athul: None. B.S. Ellsworth: None. Pituitary gland deficiency can cause infertility, metabolic dysfunction, and growth insufficiency. Many gene mutations that cause pituitary gland deficiency also cause severe developmental brain defects. During development, sonic hedgehog (SHH)signaling is crucial for the specification and differentiation of pituitary cells, with primary cilia acting as hubs for processing developmental signals. While organellescalled primary cilia play an essential role in SHH signaling, their specific influence on pituitary development remain unknown. Over the last two decades, ciliopathies have been identified as a novel category of pleiotropic diseases, characterized by overlapping phenotypes caused by dysfunction in primary cilia. Using ARL13B, a small GTPase involved in ciliary membrane dynamics and signaling, and pericentrin, a marker of centrioles, as markers of primary cilia, we explored the spatial and temporal patterns of primary cilia during pituitary gland development. Immunohistochemistry results revealed the presence of primary cilia as early as embryonic day (e)10.5. To determine if primary cilia are expressed in distinct anterior pituitarycell types, we performed co-immunohistochemistry. These studies revealed the presence of ARL13B in a subset of somatotropes, lactotropes, thyrotropes, corticotropes, and gonadotropes. These findingshighlight the potential role of primary cilia in facilitating sensory functions that may influence hormonesecretion. To investigate the role of the ciliopathy gene, Mks1, in pituitary gland development, we used the Mks1 gene trap mouse model. Mutations in MKS1 causes ciliopathies such as Bardet-Biedl, Joubert, and Meckel syndromes. The MKS1 gene is located on chromosome 17q22 in humans and encodes the MKS1 protein, which is a key factor in the transition zone of primary cilia. We examined e12.5 and e14.5 wild-type and Mks1-null mouse embryos and found that in null embryos, the pituitary gland was extremely hypoplastic and the ventral diencephalon was dysmorphic. Interestingly expression of critical transcription factors, including LHX3, PITX2, and POU1F1, which are essential for cell lineage specification and pituitary differentiation, was markedly absent in null embryos, indicating a failure of oral ectoderm to adapt apituitary fate. These findings highlight the essential role of MKS1 during pituitary morphogenesis and development. The severe morphological, molecular and cellular defects observed in Mks1-null embryos demonstrate the critical dependence of pituitary development on functional primary cilia. Our studyprovides insights into how ciliopathies, such as Bardet-Biedl and Meckel syndromes, may disrupt endocrine organogenesis through impaired ciliary function. Presentation: Saturday, July 12, 2025