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. genesis 48:540–553, 2010. © 2010 Wiley‐Liss, Inc.