Loss of Necdin impairs myosin activation and delays cell polarization

Abstract

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.