Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Abstract

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency, and 2 presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2 –/– mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4 –/– and Dchs1 –/– mouse mutants, but all animal models displayed normal commitment to anterior pituitary cell types. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

The Fuzzy planar cell polarity protein (FUZ), necessary for primary cilium formation, is essential for pituitary development

“…Aside from ciliogenesis, FUZ is also a Planar Cell Polarity (PCP) pathway effector, a pathway which we have previously examined in the pituitary in the context of receptor‐ligand FAT/DCHS protocadherins. Mutations in FAT/DCHS family result in pituitary phenotypes ranging from morphological defects of the anterior pituitary, interrupted pituitary stalk and ectopic posterior pituitary (Lodge et al, 2020 and see Voutetakis, 2021 for comprehensive review on pituitary stalk anomalies). However, these phenotypes do not overlap with what we see in Fuz −/− mutations, which appear consistent with defects in SHH signalling rather than PCP defects.…”

Cellular interactions in the pituitary stem cell niche

“…Apical protein NF2 (Merlin) and AMOTs have also been linked to upstream regulation of LATS activity [ 56 ]. Additionally, in Drosophila and some mammalian tissues, the Hippo pathway can be regulated via the atypical protocadherins Fat and Dachsous [ 56 ], although within the pituitary, mutations in FAT4 and DCHS1/DCHS2 do not appear to influence YAP/TAZ function [ 57 ]. Extracellular control of the Hippo pathway within the pituitary remains to be elucidated.…”

Advances in differential diagnosis and management of growth hormone deficiency in children

“…Furthermore an association can occur between PSIS and extrapituitary abnormalities such as biliary ciliopathy with homozygous TTC26 mutations 123 and Fanconi anaemia 119,124,125 .However, like SOD, a polygenic and multifactorial aetiology is probable, and, in one study, up to 83% of patients with sporadic PSIS have multiple heterozygous variations in genes largely affecting Notch, Shh and Wnt signalling 124 . More recent whole-exome studies from 2018 and 2020 have identified further candidate genes (for example, FAT2, DCHS1, DCHS2, ROBO2, CCDC88C, KIF14and KAT6A) 126,127 .…”