Loss of Necdin impairs myosin activation and delays cell polarization.
NDN is one of several genes inactivated in Prader-Willi syndrome (PWS), a developmental disorder characterized by obesity, hypotonia, and developmental delay. We demonstrate that loss of Necdin in murine and human fibroblasts impairs polarity initiation through a Cdc42-myosin-dependent pathway, thereby reducing cell migration. We identified defective polarization in both primary neuron cultures and in the developing limb in Ndn-null mice. Ndn-null neurons fail to activate myosin light chain and display defective polarization with respect to a brain-derived neurotrophic factor gradient. Pax3+ muscle progenitors in Ndn-null developing forelimbs display defective polarization, do not adequately migrate into the dorsal limb bud, and extensor muscles are consequently smaller. These results provide strong evidence that Necdin is a key protein regulating polarization of the cytoskeleton during development. Furthermore, this is the first demonstration of a cellular defect in PWS and suggests a novel molecular mechanism to explain neurological and muscular pathophysiologies in PWS.
Bush
Jason R
JR
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Wevrick
Rachel
R
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology*; D005347:Fibroblasts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018878:Limb Buds / Q000502:physiology; D051379:Mice; D009218:Myosins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000378:metabolism; D010766:Phosphorylation; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C069766:necdin; D009218:Myosins; D020764:cdc42 GTP-Binding Protein