The neural EGF family member CALEB/NGC mediates dendritic tree and spine complexity.
The development of dendritic arborizations and spines is essential for neuronal information processing, and abnormal dendritic structures and/or alterations in spine morphology are consistent features of neurons in patients with mental retardation. We identify the neural EGF family member CALEB/NGC as a critical mediator of dendritic tree complexity and spine formation. Overexpression of CALEB/NGC enhances dendritic branching and increases the complexity of dendritic spines and filopodia. Genetic and functional inactivation of CALEB/NGC impairs dendritic arborization and spine formation. Genetic manipulations of individual neurons in an otherwise unaffected microenvironment in the intact mouse cortex by in utero electroporation confirm these results. The EGF-like domain of CALEB/NGC drives both dendritic branching and spine morphogenesis. The phosphatidylinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway and protein kinase C (PKC) are important for CALEB/NGC-induced stimulation of dendritic branching. In contrast, CALEB/NGC-induced spine morphogenesis is independent of PI3K but depends on PKC. Thus, our findings reveal a novel switch of specificity in signaling leading to neuronal process differentiation in consecutive developmental events.
Brandt
Nicola
N
Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Franke
Kristin
K
Rasin
Mladen-Roko
MR
Baumgart
Jan
J
Vogt
Johannes
J
Khrulev
Sergey
S
Hassel
Burkhard
B
Pohl
Elena E
EE
Sestan
Nenad
N
Nitsch
Robert
R
Schumacher
Stefan
S
D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009024:Morphogenesis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics / Q000502:physiology*; D011554:Pseudopodia / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D004815:Epidermal Growth Factor; D008565:Membrane Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D011494:Protein Kinases; D011509:Proteoglycans; D058570:TOR Serine-Threonine Kinases; C403173:Cspg5 protein, mouse; C485738:Cspg5 protein, rat; C546843:mTOR protein, mouse; C546845:mTOR protein, rat