title: Phosphatidylinositol 3,4-bisphosphate regulates neurite initiation and dendrite morphogenesis via actin aggregation.
abstract: Neurite initiation is critical for neuronal morphogenesis and early neural circuit development. Recent studies showed that local actin aggregation underneath the cell membrane determined the site of neurite initiation. An immediately arising question is what signaling mechanism initiated actin aggregation. Here we demonstrate that local clustering of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), a phospholipid with relatively few known signaling functions, is necessary and sufficient for aggregating actin and promoting neuritogenesis. In contrast, the related and more extensively studied phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol (3,4,5)-trisphosphate (PIP3) molecules did not have such functions. Specifically, we showed that beads coated with PI(3,4)P2promoted actin aggregation and neurite initiation, while pharmacological interference with PI(3,4)P2synthesis inhibited both processes. PI(3,4)P2clustering occurred even when actin aggregation was pharmacologically blocked, demonstrating that PI(3,4)P2functioned as the upstream signaling molecule. Two enzymes critical for PI(3,4)P2generation, namely, SH2 domain-containing inositol 5-phosphatase and class II phosphoinositide 3-kinase α, were complementarily and non-redundantly required for actin aggregation and neuritogenesis, as well as for subsequent dendritogenesis. Finally, we demonstrate that neural Wiskott-Aldrich syndrome protein and the Arp2/3 complex functioned downstream of PI(3,4)P2to mediate neuritogenesis and dendritogenesis. Together, our results identify PI(3,4)P2as an important signaling molecule during early development and demonstrate its critical role in regulating actin aggregation and neuritogenesis.
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Shu-Xin
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Duan
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shun-Ji
authors.initials: SJ
authors.lastname: He
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Gui-Feng
authors.initials: GF
authors.lastname: Zhuang
authors.affiliation: Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000378:metabolism; D066329:Protein Aggregates; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D018129:Phosphatidylinositol Phosphates; D066329:Protein Aggregates; D051316:Wiskott-Aldrich Syndrome Protein; C060980:phosphatidylinositol 3,4-diphosphate; D019869:Phosphatidylinositol 3-Kinases; C000606436:Inppl1 protein, rat; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases