Pituitary Phenotypes of Mice Lacking the Notch Signalling Ligand Delta‐Like 1 Homologue

Abstract

The Notch signalling pathway ligand delta-like 1 homologue (Dlk1, also named Pref1) is expressed throughout the developing pituitary and becomes restricted to mostly growth hormone (GH) cells within the adult gland. We have investigated the role of Dlk1 in pituitary development and function from late embryogenesis to adulthood using a mouse model completely lacking the expression of Dlk1. We confirm that Dlk1-null mice are shorter and weigh less than wild-type littermates from late gestation, at parturition and in adulthood. A loss of Dlk1 leads to significant reduction in GH content throughout life, whereas other pituitary hormones are reduced to varying degrees depending on sex and age. Both the size of the pituitary and the proportion of hormone-producing cell populations are unchanged, suggesting that there is a reduction in hormone content per cell. In vivo challenge of mutant and wild-type littermates with growth hormone-releasing hormone and growth hormone-releasing hexapeptide shows that reduced GH secretion is unlikely to account for the reduced growth of Dlk1 knockout animals. These data suggest that loss of Dlk1 gives rise to minor pituitary defects manifesting as an age- and sex-dependent reduction in pituitary hormone contents. However, Dlk1 expression in other tissue is most likely responsible for the weight and length differences observed in mutant animals.

Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models

“…Consistent with this, Dlk1-null mice have reduced pituitary GH content (Cheung et al 2013) while Dlk1 overexpressing mice have excess pituitary Gh mRNA and circulating levels (Charalambous et al 2014b). As discussed above, Dio3 affects the levels of active TH (Hernandez et al 2006).…”

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

“…Notably, a recent study reported a reduction in GH secretion after Dlk1 deletion (40). However, a somatotroph-specific deletion of Dlk1 did not alter steady-state GH transcription, consistent with extrapituitary signaling mechanisms being involved (39).…”

“…Several previous studies have implicated DLK1 in GH regulation (38)(39)(40)(41), and also conversely GH in the regulation of DLK1 (42)(43)(44). Notably, a recent study reported a reduction in GH secretion after Dlk1 deletion (40).…”

Pituitary Gland Development and Disease

“…The Notch ligand Dll3 is expressed in corticotropes; although it is not required for corticotrope differentiation 55 . The Dlk1 Notch ligand is expressed in all hormonal cell types, and loss of Dlk1 leads to a decrease in all cell types, with the most significant reduction occurring in somatotropes 56, 57 . More studies are necessary to define the role of notch family receptors, ligands and target genes in regulating pituitary progenitor transitions to differentiation and cell specification.…”