Endocrine Abstracts

Aberrant development of the pituitary gland can result in the clinical manifestation of hypopituitarism. The Wnt/β-catenin pathway has been shown to be involved in normal organogenesis, terminal differentiation and the aetiology of pituitary tumours. However, the specific developmental roles during hypothalamic–pituitary development of some of the Wnt/β-catenin effectors, such as Tcf3, have been hampered due to the early lethality of null embryos for this gene. To overcome this, we have conditionally deleted Tcf3 (Tcf3^Fl/−;Hesx1^Cre/+) from the Hesx1-expressing cells within the early forebrain and developing pituitary gland. A low proportion of Tcf3^Fl/−;Hesx1^Cre/+ animals exhibit dwarfism indicating that deficiency in Tcf3 can lead to hypopituitarism in mice. Analyses of Tcf3^Fl/−;Hesx1^Cre/+ mutant embryos reveals a mild hyperplasia of the pituitary gland, sometimes with the mis-location of the pituitary in the pharyngeal cavity. We show that Tcf3 has a dual function and it is required in both the ventral diencephalon (VD) and anterior pituitary gland (AP). In the VD, absence of Tcf3 results in aberrant VD signaling with rostrally expanded Fgf10 and BMP4 expression domains, leading to a broader region of the oral ectoderm being specified into Rathke’s pouch. Within the developing AP, absence of Tcf3 results in increased mitotic index of periluminal Rathke’s pouch progenitors, further exacerbating the AP-hyperplasia. To assess if TCF3 is required to mediate transcriptional activation or repression of Wnt/β-catenin pathway, we studied a second murine mutant (Tcf3^ΔN/ΔN) expressing a mutant TCF3 lacking the β-catenin interacting domain, and therefore acting as a constitutive repressor. Interestingly, Tcf3^ΔN/ΔN embryos exhibit normal development of both the prospective hypothalamus and the pituitary gland throughout all developmental stages, indicating that TCF3-repressing activity is essential for hypothalamic–pituitary development. Providing a translational impact to this research, we report the identification of two novel mutation in hTCF3 that compromises TCF3-repressing activity in a patient with septo-optic dysplasia (SOD), suggesting a causative role of TCF3 in SOD. In summary, our research demonstrates a critical role for the Wnt/β-catenin effector Tcf3 during early development of the pituitary–hypothalamic axis in mice and humans.