Phosphatidylinositol 3,4-bisphosphate Regulates Neurite Initiation and Dendrite Morphogenesis Via Actin Aggregation

Overview

Journal Cell Res

Specialty Cell Biology

Date 2017 Jan 21

PMID 28106075

Citations 19

Authors

Shu-Xin Zhang

Li-Hui Duan

Shun-Ji He

Gui-Feng Zhuang

Xiang Yu

Affiliations

Soon will be listed here.

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)P), 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 (PIP) molecules did not have such functions. Specifically, we showed that beads coated with PI(3,4)P promoted actin aggregation and neurite initiation, while pharmacological interference with PI(3,4)P synthesis inhibited both processes. PI(3,4)P clustering occurred even when actin aggregation was pharmacologically blocked, demonstrating that PI(3,4)P functioned as the upstream signaling molecule. Two enzymes critical for PI(3,4)P generation, 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)P to mediate neuritogenesis and dendritogenesis. Together, our results identify PI(3,4)P as an important signaling molecule during early development and demonstrate its critical role in regulating actin aggregation and neuritogenesis.

Citing Articles

Attenuated cerebellar phenotypes in Inpp4a truncation mutants with preserved phosphatase activity.

Tran D, Yoshioka N, Bizen N, Mori-Ochiai Y, Yano M, Yanai S Dis Model Mech. 2023; 16(7).

PMID: 37415561 PMC: 10399444. DOI: 10.1242/dmm.050169.

The cytoplasmic localization of ADNP through 14-3-3 promotes sex-dependent neuronal morphogenesis, cortical connectivity, and calcium signaling.

Bennison S, Blazejewski S, Liu X, Hacohen-Kleiman G, Sragovich S, Zoidou S Mol Psychiatry. 2023; 28(5):1946-1959.

PMID: 36631597 DOI: 10.1038/s41380-022-01939-3.

PtdIns(3,4)P2, Lamellipodin, and VASP coordinate actin dynamics during phagocytosis in macrophages.

Montano-Rendon F, Walpole G, Krause M, Hammond G, Grinstein S, Fairn G J Cell Biol. 2022; 221(11).

PMID: 36165850 PMC: 9521245. DOI: 10.1083/jcb.202207042.

Serum exosomal coronin 1A and dynamin 2 as neural tube defect biomarkers.

Wang Y, Ma L, Jia S, Liu D, Gu H, Wei X J Mol Med (Berl). 2022; 100(9):1307-1319.

PMID: 35915349 PMC: 9402777. DOI: 10.1007/s00109-022-02236-w.

Striking a balance: PIP and PIP signaling in neuronal health and disease.

Tariq K, Luikart B Explor Neuroprotective Ther. 2022; 1:86-100.

PMID: 35098253 PMC: 8797975. DOI: 10.37349/ent.2021.00008.

References

Bae Y, Lee T, Park J, Hur J, Kim Y, Heo K . Identification of a compound that directly stimulates phospholipase C activity. Mol Pharmacol. 2003; 63(5):1043-50. DOI: 10.1124/mol.63.5.1043. View

Dowler S, Currie R, Campbell D, Deak M, Kular G, Downes C . Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem J. 2000; 351(Pt 1):19-31. PMC: 1221362. DOI: 10.1042/0264-6021:3510019. View

Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B . The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010; 11(5):329-41. DOI: 10.1038/nrm2882. View

Kwiatkowski A, Rubinson D, Dent E, van Veen J, Leslie J, Zhang J . Ena/VASP Is Required for neuritogenesis in the developing cortex. Neuron. 2007; 56(3):441-55. DOI: 10.1016/j.neuron.2007.09.008. View

Kimberley McAllister A . Dynamic aspects of CNS synapse formation. Annu Rev Neurosci. 2007; 30:425-50. PMC: 3251656. DOI: 10.1146/annurev.neuro.29.051605.112830. View

Ozaki S, Dewald D, Shope J, Chen J, Prestwich G . Intracellular delivery of phosphoinositides and inositol phosphates using polyamine carriers. Proc Natl Acad Sci U S A. 2000; 97(21):11286-91. PMC: 17192. DOI: 10.1073/pnas.210197897. View

Shen K, Scheiffele P . Genetics and cell biology of building specific synaptic connectivity. Annu Rev Neurosci. 2010; 33:473-507. PMC: 3082953. DOI: 10.1146/annurev.neuro.051508.135302. View

Bae Y, Ding Z, Das T, Wells A, Gertler F, Roy P . Profilin1 regulates PI(3,4)P2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells. Proc Natl Acad Sci U S A. 2010; 107(50):21547-52. PMC: 3003040. DOI: 10.1073/pnas.1002309107. View

Wada T, Sasaoka T, Funaki M, Hori H, Murakami S, Ishiki M . Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity. Mol Cell Biol. 2001; 21(5):1633-46. PMC: 86709. DOI: 10.1128/MCB.21.5.1633-1646.2001. View

10.

Yoshinaga S, Ohkubo T, Sasaki S, Nuriya M, Ogawa Y, Yasui M . A phosphatidylinositol lipids system, lamellipodin, and Ena/VASP regulate dynamic morphology of multipolar migrating cells in the developing cerebral cortex. J Neurosci. 2012; 32(34):11643-56. PMC: 6703763. DOI: 10.1523/JNEUROSCI.0738-12.2012. View

11.

McAllister A, Katz L, Lo D . Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth. Neuron. 1997; 18(5):767-78. DOI: 10.1016/s0896-6273(00)80316-5. View

12.

Gassama-Diagne A, Yu W, Ter Beest M, Martin-Belmonte F, Kierbel A, Engel J . Phosphatidylinositol-3,4,5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nat Cell Biol. 2006; 8(9):963-70. DOI: 10.1038/ncb1461. View

13.

Li H, Marshall A . Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling. Cell Signal. 2015; 27(9):1789-98. DOI: 10.1016/j.cellsig.2015.05.013. View

14.

Michael M, Vehlow A, Navarro C, Krause M . c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis. Curr Biol. 2010; 20(9):783-91. PMC: 2946563. DOI: 10.1016/j.cub.2010.03.048. View

15.

Ward M, Wu J, Rao Y . Visualization of spatially and temporally regulated N-WASP activity during cytoskeletal reorganization in living cells. Proc Natl Acad Sci U S A. 2004; 101(4):970-4. PMC: 327126. DOI: 10.1073/pnas.0306258101. View

16.

Papayannopoulos V, Co C, Prehoda K, Snapper S, Taunton J, Lim W . A polybasic motif allows N-WASP to act as a sensor of PIP(2) density. Mol Cell. 2005; 17(2):181-91. DOI: 10.1016/j.molcel.2004.11.054. View

17.

Skwarek L, Boulianne G . Great expectations for PIP: phosphoinositides as regulators of signaling during development and disease. Dev Cell. 2009; 16(1):12-20. DOI: 10.1016/j.devcel.2008.12.006. View

18.

Flynn K . The cytoskeleton and neurite initiation. Bioarchitecture. 2013; 3(4):86-109. PMC: 4201609. DOI: 10.4161/bioa.26259. View

19.

Stradal T, Rottner K, Disanza A, Confalonieri S, Innocenti M, Scita G . Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol. 2004; 14(6):303-11. DOI: 10.1016/j.tcb.2004.04.007. View

20.

Flynn K, Hellal F, Neukirchen D, Jacob S, Tahirovic S, Dupraz S . ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron. 2012; 76(6):1091-107. DOI: 10.1016/j.neuron.2012.09.038. View