Research Article: IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice

Date Published: January 11, 2017

Publisher: Public Library of Science

Author(s): Lyvianne Decourtye, Erik Mire, Maud Clemessy, Victor Heurtier, Tatiana Ledent, Iain C. Robinson, Patrice Mollard, Jacques Epelbaum, Michael J. Meaney, Sonia Garel, Yves Le Bouc, Laurent Kappeler, Raul M. Luque.


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 postnatal period with programming of the growth trajectory.

Partial Text

Normal development of both cognitive and somatic functions requires suitable nutrition of the developing fetus and newborns during the perinatal period [1]. Indeed, insufficient food supplies during the early postnatal period affect body growth as well as the risk of developing cardiovascular and metabolic diseases in adulthood. This is in agreement with the developmental origin of health and adult diseases (DOHaD), particularly after intrauterine growth retardation, which accounts for 5% of births [2]. This programming of adult diseases, which has been validated in various animal models as well as in human populations [1,3,4,5], further highlights the importance of mechanisms that link the sensing of nutritional state to a shift in the developmental trajectory, which is strongly integrated with that of linear growth.

Here, we show that IGF-I may be involved in axon elongation in a specific subpopulation of hypothalamus neurons. Indeed, the present study indicates that i) IGF-I preferentially stimulates axon growth of GHRH neurons in arcuate nucleus explants of normally fed pups during lactation; ii) IGF-1 stimulation involves the two main signaling pathways PI3K/AKT and ERK/MEK, with greater involvement of the PI3K/AKT pathway; and iii) GHRH neurons harvested from underfed pups during lactation and cultivated in vitro grow less and become insensitive to the growth promoting effect of IGF-I. This loss of response does not involve an alteration of the IGF-1R or ERK/MEK pathway, but is associated with a defect in AKT activation. Finally, iv) nutritional restriction during lactation, which is associated with permanent growth retardation and later metabolic alterations, is associated with lower IGF-I plasma levels and a change of the body growth trajectory. It is preceded by delayed axon elongation of GHRH neurons during the first 10 days of life, a critical developmental window. These physiological outcomes are in agreement with the tight control of IGF-I levels by nutritional supplies.




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