Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.
Prader-Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavioral outcomes of PWS, an understanding of its effects on the development of hypothalamic circuits remains elusive. Here, we show that mice lacking Magel2, one of the genes responsible for the etiology of PWS, display an abnormal development of ARH axonal projections. Notably, the density of anorexigenic α-melanocyte-stimulating hormone axons was reduced in adult Magel2-null mice, while the density of orexigenic agouti-related peptide fibers in the mutant mice appeared identical to that in control mice. On the basis of previous findings showing a pivotal role for metabolic hormones in hypothalamic development, we also measured leptin and ghrelin levels in Magel2-null and control neonates and found that mutant mice have normal leptin and ghrelin levels. In vitro experiments show that Magel2 directly promotes axon growth. Together, these findings suggest that a loss of Magel2 leads to the disruption of hypothalamic feeding circuits, an effect that appears to be independent of the neurodevelopmental effects of leptin and ghrelin and likely involves a direct neurotrophic effect of Magel2.
The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Department of Pediatrics, Los Angeles, CA 90027, USA.|Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille 59045, France.
Julien
J
Maillard
The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Department of Pediatrics, Los Angeles, CA 90027, USA.
Soyoung
S
Park
The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Department of Pediatrics, Los Angeles, CA 90027, USA.
Sophie
S
Croizier
Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille 59045, France.
Charlotte
C
Vanacker
The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Department of Pediatrics, Los Angeles, CA 90027, USA.
Joshua H
JH
Cook
Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille 59045, France.
Vincent
V
Prevot
Maithe
M
Tauber
The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Department of Pediatrics, Los Angeles, CA 90027, USA sbouret@chla.usc.edu.|Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille 59045, France.
Sebastien G
SG
Bouret
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000196:embryology*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D011218:Prader-Willi Syndrome / Q000196:embryology / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
D000951:Antigens, Neoplasm; D054439:Ghrelin; D020738:Leptin; D011506:Proteins; C403091:Magel2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins