SAT-115 - Loss of the Ciliopathy Protein, MKS1, Impairs Pituitary Gland Development

Pituitary gland deficiency results in impaired function of multiple peripheral endocrine organs, resulting in deficiencies in growth, metabolism, reproduction, stress responses, and lactation. Defects in pituitary gland development can cause combined pituitary hormone deficiency (CPHD), a condition that can be associated with midline abnormalities including septo-optic dysplasia (SOD), holoprosencephaly (HPE), and cleft palate. Proper pituitary organogenesis relies on highly regulated signaling interactions between the oral ectoderm and ventral diencephalon, with Sonic hedgehog (SHH) signaling serving as a key regulator in pituitary gland patterning and development. SHH signal transduction requires intact primary cilia, a microtubule-based organelle found on apical surfaces of most vertebrate cells. In this study, we investigate the role of MKS1, a core transition zone component of primary cilia mutated in well-known ciliopathies including Meckel, Joubert and Bardet-Biedl syndrome, during pituitary development. Using the Mks1+/tm1b LacZ reporter allele, we mapped endogenous Mks1 expression from embryonic day (E)9.5–E12.5. LacZ expression was detectable within the developing Rathke’s pouch and ventral diencephalon, with strongest signal in the ventral diencephalon and infundibulum—regions critical for initiating signaling to the developing pituitary gland. We next analyzed Mks1-null (Mks1tm1a/tm1a) embryos from E9.5–E15.5. Histological and immunohistochemistry analyses revealed a complete failure of definitive Rathke’s pouch formation, with only an irregular oral ectodermal invagination that failed to progress, accompanied by absence of the infundibulum. Immunofluorescence analysis using ARL13B, a primary cilia membrane marker, demonstrated near-complete loss of primary cilia in the ventral diencephalon and marked reduction in the oral ectoderm. Consistent with primary ciliary dysfunction, SHH, BMP4, and FGF8 signaling domains were spatially disrupted, accompanied by elevated Gli1 expression, indicating deregulated Hedgehog pathway output. Failure of pituitary induction was further supported by variable PITX2 expression and complete loss of LHX3, demonstrating a failure of oral ectoderm to establish a pituitary fate. Together, these findings provide mechanistic insight into how ciliopathies like Meckel and Joubert syndromes may disrupt endocrine organogenesis through impaired ciliary function.

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