ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms.
Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.
Krivosheya
Daria
D
Department of Psychiatry, the Brain Research Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Tapia
Lucia
L
Levinson
Joshua N
JN
Huang
Kun
K
Kang
Yunhee
Y
Hines
Rochelle
R
Ting
Annie K
AK
Craig
Ann Marie
AM
Mei
Lin
L
Bamji
Shernaz X
SX
El-Husseini
Alaa
A
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D020880:Neuregulins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism
D066246:ErbB Receptors; D020880:Neuregulins; D019869:Phosphatidylinositol 3-Kinases; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat