The cytoplasmic localization of ADNP through 14-3-3 promotes sex-dependent neuronal morphogenesis, cortical connectivity, and calcium signaling
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…
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Mutations in MEF2C, BCL11A, RAI1, and ADNP can disrupt cortical and subcortical network architecture and function, often associated with syndromic ASD.
“Mutations in these genes can disrupt cortical and subcortical network architecture and function, often associated with syndromic ASD (Bennison et al., 2023).”
From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Bennison et al., 2023
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“Treatment of cells in culture with NAP has been shown to promote or rescue neurite outgrowth [31, 32], enhance microtubule dynamics and Tau-microtubule association [29, 33, 34], and interact with microtubule end binding protein (EB3) to enhance dendritic spine formation [35, 36].”
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Teter, O. M., McQuade, A., Hagan, V., Liang, W., Dräger, N. M., Sattler, S. M., Holmes, B. B., Castillo, V. C., Papakis, V., Leng, K., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-02997-z · Cited by 38 · see citing works
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“Mutations in these genes can disrupt cortical and subcortical network architecture and function, often associated with syndromic ASD (Bennison et al., 2023).”
- Authors
- Bennison, S. A., Blazejewski, S. M., Liu, X., Hacohen-Kleiman, G., Sragovich, S., Zoidou, S., Touloumi, O., Grigoriadis, N., Gozes, I., & Toyo-oka, K.
- Affiliations
- Drexel University (US)
- Tel Aviv University (IL)
- Aristotle University of Thessaloniki (GR)
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2023-01-11
- Volume
- 28
- Issue
- 5
- Pages
- 1946-1959
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W4315644826
- Cited by
- 42
- References
- 7
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 16 · 2023: 10
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS096098-01A1, F31NS113404-01A1)
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (F31HD103405-01A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ADNP, 14-3-3 proteins, cytoplasmic localization, neurite outgrowth, neuronal morphogenesis, sex differences, autism spectrum disorder, phosphorylation-dependent binding, cortical connectivity, interhemispheric connectivity, layer 2/3 pyramidal neurons, somatosensory cortex, axon length
- MeSH terms
- Autism Spectrum Disorder, Animals, Calcium, Cerebral Cortex, Cytoplasm, Dendrites, Female, Humans, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Phosphorylation, Neurites, Pyramidal Cells, Homeodomain Proteins, Calcium Signaling, 14-3-3 Proteins, Mice, Neurogenesis
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