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IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice
Lyvianne Decourtye1, Erik Mire1, Maud Clemessy1
1Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS 938, Centre de Recherche St-Antoine (CRSA), Paris, France.
Insights
Early life nutrition impacts growth by altering growth hormone (GH) signaling. Insulin-like growth factor I (IGF-I) is crucial for developing GH-releasing hormone (GHRH) neuron connections, but underfeeding disrupts this process.
Area of Science:
- Neuroendocrinology
- Developmental Biology
- Nutritional Science
Background:
- Perinatal nutrition significantly influences an organism's growth trajectory.
- The somatotropic axis, regulated by growth hormone (GH) and growth hormone-releasing hormone (GHRH), controls body growth.
- GHRH neurons in the hypothalamus are critical for GH secretion.
Purpose of the Study:
- To investigate how early postnatal dietary restriction affects the development of the somatotropic axis.
- To determine the role of insulin-like growth factor I (IGF-I) in GHRH neuron development during critical growth periods.
Main Methods:
- Mice pups were subjected to dietary restriction during lactation.
- Plasma IGF-I levels and median eminence innervation by GHRH axons were assessed.
- In vitro arcuate nucleus explant cultures were used to study IGF-I's effect on GHRH neuron axon elongation.
- Molecular analyses, including AKT activation, were performed.
Main Results:
- Underfed pups exhibited reduced plasma IGF-I levels and decreased GHRH axon innervation.
- IGF-I selectively stimulated GHRH neuron axon elongation in vitro from normally fed pups.
- GHRH neurons from underfed pups lost their responsiveness to IGF-I.
- Nutritional restriction impaired AKT activation in GHRH neurons.
Conclusions:
- Early postnatal underfeeding permanently alters somatotropic axis development.
- IGF-I plays a critical, cell-selective role in GHRH neuron axon growth.
- Impaired IGF-I signaling due to undernutrition disrupts growth programming by affecting GHRH neuron development.
Abstract:
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.
