Glis3 as a critical regulator of Pit1-lineages and renal functions

The Krüppel-like GLIS3 transcription factor acts as an effector on the sonic hedgehog (Shh) pathway, regulating several biological processes and the development and postnatal function of various tissues. Given the major role of Shh signaling during the differentiation and anterior/posterior patterning of the adenohypophysis (AH) anlage, we investigated the potential role of glis3 during AH development in the zebrafish model. Glis3KD embryos exhibited increased expression of early AH-inductive genes lim3 and nkx2.2a, along with an expansion of pit1-positive precursors. This shift led to an overproduction of lactotropes, somatolactotropes, and thyrotropes, at the expense of somatotropes, corticotropes, and melanotropes. The most striking difference is the hyperprolactinemia observed in glis3KD larvae, with transcript and protein levels increased by approximately 30-fold and threefold, respectively, compared to controls. As a consequence of the primary role for prolactin in controlling fish osmoregulation, glis3KD larvae exhibited the upregulation of ionocytes expressed in gills and pronephric ducts. Furthermore, glis3KD larvae presented abnormal pronephric primary cilia and glomerular cysts in keeping with the established role of GLIS3 in ciliopathies and polycystic kidney disease. In conclusion, glis3 action appears fundamental to set an adequate number of pit1-precursors and renal function. KEY MESSAGES: Glis3 regulates pituitary cell fate by balancing pit1-positive precursors. Glis3 knockdown leads to hyperprolactinemia and altered osmoregulatory mechanisms. Glis3 is essential for normal cilia structure and pronephric kidney function.