Genetic requirement for Esrp1/2 in vertebrate pituitary morphogenesis

The pituitary gland produces several hormones that regulate growth, metabolism, stress response, reproduction, and homeostasis. Congenital hypopituitarism is a deficiency in one or more pituitary hormones and encompasses a spectrum of clinical conditions. The pituitary has a complex embryonic origin with the oral ectoderm contributing the anterior lobe, and the neural ectoderm generating the posterior lobe. Pituitary abnormalities and growth deficiencies are associated with cleft palate however the developmental genetic connection between pituitary and orofacial cleft malformations remains to be determined. The epithelial RNA splicing regulators Esrp1 and Esrp2 are required for orofacial development in zebrafish, mice, and humans, and loss of function of these genes results in a cleft palate. Here we present a detailed developmental analysis of the genetic requirement for Esrp1/2 in pituitary morphogenesis in mouse and zebrafish. Further, we describe a patient with cleft palate and hypopituitarism that harbors a nucleotide variant in the RNA binding domain of ESRP2. The discovery of this key function for Esrp1/2 in pituitary formation has significant fundamental and clinical implications for understanding congenital hypopituitarism and craniofacial anomalies.