Abstract
Diverse clustered protocadherins are thought to function in neurite morphogenesis and neuronal connectivity in the brain. Here, we report that the protocadherin alpha (Pcdha) gene cluster regulates neuronal migration during cortical development and cytoskeletal dynamics in primary cortical culture through the WAVE (Wiskott-Aldrich syndrome family verprolin homologous protein, also known as Wasf) complex. In addition, overexpression of proline-rich tyrosine kinase 2 (Pyk2, also known as Ptk2b, Cakβ, Raftk, Fak2, and Cadtk), a non-receptor cell-adhesion kinase and scaffold protein downstream of Pcdhα, impairs cortical neuron migration via inactivation of the small GTPase Rac1. Thus, we define a molecular Pcdhα/WAVE/Pyk2/Rac1 axis from protocadherin cell-surface receptors to actin cytoskeletal dynamics in cortical neuron migration and dendrite morphogenesis in mouse brain.
Highlights
The human brain contains approximately 86 billion neurons, and each neuron engages in several thousand specific synaptic connections, resulting in complex neural networks with over 1015 specific connections
Immunostaining with an antibody against alpha constant domain revealed that protocadherin alpha (Pcdha) proteins are expressed in all cortical regions and most prominently in the intermediate zone and marginal zone (IZ and MZ) of the developing neocortex (Figure 1C)
Pcdha knockdown with two independent short-hairpin RNA (shRNA), each targeting a distinct subdomain of the constant region by in utero electroporation (IUE), revealed a significant decrease of migrating neurons in the cortical plate (CP) and a concomitant increase within the lower intermediate zone, suggesting defects in multipolar migration (Figure 1D and Figure 1—figure supplement 1B)
Summary
The human brain contains approximately 86 billion neurons, and each neuron engages in several thousand specific synaptic connections, resulting in complex neural networks with over 1015 specific connections. It inhibits an enzyme known as Pyk, which increases the activity of another enzyme called Rac GTPase, that further activates WAVE This results in the WAVE complex interacting with the internal skeleton inside the neurons and dendrites, which regulates the ability of these cells to migrate and of the dendrites to avoid each other. Mutations in the genes of clustered protocadherins increase the risk of these disorders By showing how these proteins help to regulate the migration and connectivity of neurons, Fan, Lu et al add to our understanding of brain development in health and disease. Neuroscience segment, and a juxtamembrane variable cytoplasmic domain (VCD) (Shonubi et al, 2015; Wu and Maniatis, 1999), whereas the three constant exons encode a common membrane-distal constant domain (CD) of all Pcdha proteins (Figure 1A) This suggests that diverse extracellular cues converge on a single intracellular signaling pathway. Given that actin cytoskeletal dynamics are central for neurite morphogenesis and neuronal migration, our findings have interesting implications for mechanisms of Pcdha functions in dendrite self-avoidance and neuronal self/nonself recognition in normal brain development as well as aberrant neuron migration and dendrite morphogenesis underlying complex neurodevelopmental diseases
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