Journal article
The cytoplasmic localization of ADNP through 14-3-3 promotes sex-dependent neuronal morphogenesis, cortical connectivity, and calcium signaling
Molecular psychiatry
11 Jan 2023
PMID: 36631597
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Defective neuritogenesis is a contributing pathogenic mechanism underlying a variety of neurodevelopmental disorders. Single gene mutations in activity-dependent neuroprotective protein (ADNP) are the most frequent among autism spectrum disorders (ASDs) leading to the ADNP syndrome. Previous studies showed that during neuritogenesis, Adnp localizes to the cytoplasm/neurites, and Adnp knockdown inhibits neuritogenesis in culture. Here, we hypothesized that Adnp is localized in the cytoplasm during neurite formation and that this process is mediated by 14-3-3. Indeed, applying the 14-3-3 inhibitor, difopein, blocked Adnp cytoplasmic localization. Furthermore, co-immunoprecipitations showed that Adnp bound 14-3-3 proteins and proteomic analysis identified several potential phosphorylation-dependent Adnp/14-3-3 binding sites. We further discovered that knockdown of Adnp using in utero electroporation of mouse layer 2/3 pyramidal neurons in the somatosensory cortex led to previously unreported changes in neurite formation beginning at P0. Defects were sustained throughout development, the most notable included increased basal dendrite number and axon length. Paralleling the observed morphological aberrations, ex vivo calcium imaging revealed that Adnp deficient neurons had greater and more frequent spontaneous calcium influx in female mice. GRAPHIC, a novel synaptic tracing technology substantiated this finding, revealing increased interhemispheric connectivity between female Adnp deficient layer 2/3 pyramidal neurons. We conclude that Adnp is localized to the cytoplasm by 14-3-3 proteins, where it regulates neurite formation, maturation, and functional cortical connectivity significantly building on our current understanding of Adnp function and the etiology of ADNP syndrome.
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Details
- Title
- The cytoplasmic localization of ADNP through 14-3-3 promotes sex-dependent neuronal morphogenesis, cortical connectivity, and calcium signaling
- Creators
- Sarah A Bennison - Drexel UniversitySara M Blazejewski - Drexel UniversityXiaonan Liu - Drexel UniversityGal Hacohen-Kleiman - Tel Aviv UniversityShlomo Sragovich - Tel Aviv UniversitySofia Zoidou - Aristotle University of ThessalonikiOlga Touloumi - Aristotle University of ThessalonikiNikolaos Grigoriadis - Aristotle University of ThessalonikiIllana Gozes - Tel Aviv UniversityKazuhito Toyo-Oka - Drexel University
- Publication Details
- Molecular psychiatry
- Publisher
- Springer Nature
- Grant note
- F31NS113404-01A1 / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS096098-01A1 / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) F31HD103405-01A1 / U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) R01 NS096098 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pharmacology and Physiology
- Web of Science ID
- WOS:000912256600001
- Scopus ID
- 2-s2.0-85146097997
- Other Identifier
- 991020099922104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Neurosciences
- Psychiatry