Regulation of neuronal morphogenesis by 14-3-3epsilon (Ywhae) via the microtubule binding protein, doublecortin.
17p13.3 microduplication syndrome is a newly identified genetic disorder characterized by duplications in the 17p13.3 chromosome locus, resulting in a variety of disorders including autism spectrum disorder (ASD). Importantly, a minimum duplication region has been defined, and this region exclusively contains the gene encoding 14-3-3ε. Furthermore, duplication of this minimum region is strongly associated with the appearance of ASD in human patients, thus implicating the overexpression of 14-3-3ε in ASD. Using in vitro and in vivo techniques, we have found that 14-3-3ε binds to the microtubule binding protein doublecortin preventing its degradation. We also found that 14-3-3ε overexpression disrupts neurite formation by preventing the invasion of microtubules into primitive neurites, which can be rescued by the knockdown of doublecortin. To analyse the function of 14-3-3ε in neurite formation, we used 14-3-3ε flox mice and found that 14-3-3ε deficiency results in an increase in neurite formation. Our findings provide the first evidence of cellular pathology in 17p13.3 microduplication syndrome.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA USA.
Brett
B
Cornell
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA USA.
Tomoka
T
Wachi
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA USA.
Vladimir
V
Zhukarev
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA USA.
Kazuhito
K
Toyo-Oka
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics; D002352:Carrier Proteins; D002872:Chromosome Deletion; D000089622:Doublecortin Domain Proteins; D020440:Gene Duplication; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009024:Morphogenesis; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
D048948:14-3-3 Proteins; D002352:Carrier Proteins; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C576823:Ywhae protein, mouse