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Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip+/−) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip+/− mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip+/− mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip+/− mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip+/− mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip+/− mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip+/− mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model.

Nutrition plays a critical role in programming and shaping linear growth during early postnatal life through direct action on the development of the neuroendocrine somatotropic (GH/IGF-1) axis. IGF-1 is a key factor in modulating the programming of linear growth during this period. Notably, IGF-1 preferentially stimulates axonal growth of GHRH neurons in the arcuate nucleus of the hypothalamus (Arc), which is crucial for the proliferation of somatotroph progenitors in the pituitary, thus influencing later GH secretory capacity. However, other nutrition-related hormones may also be involved. Among them, insulin shares several structural and functional similarities with IGF-1, as well as downstream signaling effectors. We investigated the role of insulin in the control of Arc axonal growth using an in vitro model of arcuate explants culture and a cell-type specific approach (GHRH-eGFP mice) under both physiological conditions (normally fed pups) and those of dietary restriction (underfed pups). Our data suggest that insulin failed to directly control axonal growth of Arc neurons or influence specific IGF-1-mediated effects on GHRH neurons. Insulin may act on neuronal welfare, which appears to be dependent on neuronal sub-populations and is influenced by the nutritional status of pups in which Arc neurons develop.

International audience; Nutrition during the perinatal period programs body growth. Growth hormone (GH) secretion from the pituitary regulates body growth and is controlled by Growth Hormone Releasing Hormone (GHRH) neurons located in the arcuate nucleus of the hypothalamus. We observed that dietary restriction during the early postnatal period (i.e. lactation) in mice influences postnatal growth by permanently altering the development of the somatotropic axis in the pituitary gland. This alteration may be due to a lack of GHRH signaling during this critical developmental period. Indeed, underfed pups showed decreased insulin-like growth factor I (IGF-I) plasma levels, which are associated with lower innervation of the median eminence by GHRH axons at 10 days of age relative to normally fed pups. IGF-I preferentially stimulated axon elongation of GHRH neurons in in vitro arcuate explant cultures from 7 day-old normally fed pups. This IGF-I stimulating effect was selective since other arcuate neurons visualized concomitantly by neurofilament labeling, or AgRP immunochemistry, did not significantly respond to IGF-I stimulation. Moreover, GHRH neurons in explants from age-matched underfed pups lost the capacity to respond to IGF-I stimulation. Molecular analyses indicated that nutritional restriction was associated with impaired activation of AKT. These results highlight a role for IGF-I in axon elongation that appears to be cell selective and participates in the complex cellular mechanisms that link underfeeding during the early postna-tal period with programming of the growth trajectory.

International audience; Organism development is controlled by both genetic programs and the environment to insure a reproductive success as adults. Linear growth is an important part of the development and is mostly controlled by genetic factors. However, the variability of height in a given species does not seem to be specifically associated with SNP. This suggests that environment may play a crucial role. In agreement, an important part of height-related genes present CpG island in their proximal promoter, indicating potential involvement of epigenetic mechanisms. In mammals, the linear growth is regulated by the IGF system, with IGF-I and IGF-II during the fetal period, and IGF-I being included within the somatotropic axis during the postnatal period. Nutrition during the lactating period programs linear growth and adult size through a modulation of the somatotropic axis development and of the setting of its activity later on. The study of underlying mechanisms suggest two waves of programming, which involve both structural adaptation during the early postnatal period and permanent functional adaptation in adulthood. The former may involve a direct stimulation of axon growth of GHRH neurons by IGF-I in first weeks of life while the latter could involve permanent epigenetic modifications in adulthood.; Le développement de l’organisme est contrôlé à la fois par des programmes génétiques et par l’environnement afin d’assurer un succès reproductif à l’âge adulte. La croissance staturale est une partie importante du développement et est principalement contrôlée par des facteurs génétiques. Cependant, la variabilité de la taille chez une espèce donnée ne semble pas être entièrement sous la dépendance du background génétique. Ceci suggère que l’environnement pourrait jouer un rôle crucial. En accord avec cela, une proportion importante des gènes liés à la croissance présente un îlot CpG dans leur promoteur proximal, ce qui indique l’implication potentielle de mécanismes épigénétiques. Chez les mammifères, la croissance staturale est régulée par le système IGF, avec l’IGF-I et IGF-II durant la période fœtale et l’IGF-I étant inclus dans l’axe somatotrope lors la période postnatale. La nutrition pendant la période transitoire qu’est l’allaitement programme la croissance staturale et la taille adulte par une modulation du développement de l’axe somatotrope et de son activité à l’âge adulte. L’étude des mécanismes sous-jacents suggère deux vagues de programmation, qui impliquent à la fois une adaptation structurelle en période postnatale précoce et une adaptation fonctionnelle permanente chez l’adulte. La première semble impliquer une stimulation directe de la croissance axonale des neurones GHRH par l’IGF-I dans les premières semaines de vie, alors que la seconde pourrait impliquer des modifications épigénétiques permanentes à l’âge adulte.

[This corrects the article DOI: 10.1371/journal.pone.0170083.].