Preso regulation of dendritic outgrowth through PI(4,5)P2-dependent PDZ interaction with βPix

• Published in: The European journal of neuroscience 2012-07, Vol.36 (1), p.1960-1970
• Main Authors: Mo, Jiwon, Lee, Dongmin, Hong, Soontaek, Han, Seungrie, Yeo, Hyojin, Sun, Woong, Choi, Sukwoo, Kim, Hyun, Lee, Hyun Woo
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Animals; Cells, Cultured; Dendrites - metabolism; dendritic growth cones; Dendritic spines; Disks Large Homolog 4 Protein; ezrin; F-actin; FERM domain; Growth cones; Growth Cones - metabolism; Guanine Nucleotide Exchange Factors - metabolism; Guanosinetriphosphatase; HEK293 Cells; hippocampal neuron; Humans; Inositol; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - metabolism; moesin; Morphogenesis; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous system; Neural networks; Neurons - cytology; Neurons - metabolism; PDZ Domains; Phosphatidylinositol 4,5-diphosphate; Phosphatidylinositol 4,5-Diphosphate - metabolism; Postsynaptic density proteins; radixin; Rats; Rats, Sprague-Dawley; Rho Guanine Nucleotide Exchange Factors; RNA, Small Interfering; Spine; Zonula occludens-1 protein
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2012.08124.x

In neuronal development, dendritic outgrowth and arborization are important for the establishment of neural circuit formation. A previous study reported that PSD‐95‐interacting regulator of spine morphogenesis (Preso) formed a complex with PAK‐interacting exchange factor‐beta (βPix) via PSD‐95/Dlg/ZO‐1 (PDZ) interaction. Here, we report that Preso and its binding protein, βPix, are localized in dendritic growth cones. Knockdown and dominant‐negative inhibition of Preso in cultured neurons markedly reduced the dendritic outgrowth but not branching, and led to a decrease in the intensity of βPix and F‐actin in neuronal dendritic tips. Moreover, phosphatidylinositol 4,5‐bisphosphate (PIP2) induced a conformational change in Preso toward the open PDZ domain and enhanced the interaction with βPix. In addition, the Preso band 4.1 protein, ezrin, radixin and moesin (FERM) domain mutant is unable to interact with PIP2 and it did not rescue the Preso‐knockdown effect. These results indicate that PIP2 is a key signalling molecule that regulates dendritic outgrowth through activation of small GTPase signalling via interaction between Preso and βPix. Preso (PSD‐95‐interacting regulator of spine morphogenesis) forms a complex with βPix (PAK‐interacting exchange factor beta) via PDZ interaction in dendritic growth cones and its interaction is required for neuronal dendritic development through the maintenance of F‐actin by activation of small GTPase signalling. Phosphatidyl inositol 4,5‐bisphosphate binding to FERM domain of Preso induces its conformational change toward open PDZ domain and enhances the interaction with βPix.