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.
Highlights
The anterior pituitary gland has a central role in physiology, regulating various processes such as growth, lactation and pregnancy, reproduction, metabolism, and response to stress
The nose-tail length of delta-like 1 homologue (Dlk1)-null mice at 14 weeks of age was reduced compared to wild-type littermates in both male and female mice (Fig. 2A, ii), consistent with them having a reduction in body size from birth without subsequent catch-up growth
Because Dlk1 mutant neonates have a reduced weight at birth and Dlk1 has previously been shown to be expressed in the embryonic vessels of the placenta, we examined the placentas of Dlk1 mutant mice for any obvious aetiologies for intrauterine growth restriction
Summary
The anterior pituitary gland has a central role in physiology, regulating various processes such as growth, lactation and pregnancy, reproduction, metabolism, and response to stress. The five different hormone-producing cell types within the gland are specified during embryogenesis by a cascade of transcription factors and signalling pathways [1], the number of cells of each population increases after birth [2] and can vary throughout life in response to physiological demand [3]. Notch effector RBPjj in the developing mouse embryo leads to premature differentiation of corticotrophs and, overexpression of the active Notch receptor inhibits terminal differentiation [11]. Taken together, this evidence points towards Notch signalling as a regulator of differentiation timing within pituitary hormone cell types. We have expanded on these previous studies by assessing the effect of loss of Dlk on growth and pituitary hormones, in particular investigating whether the growth retardation could be accounted for by a deficient secretion of GH
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