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Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

ABSTRACT: Large-scale genomic screenings greatly advanced our understanding of the genetic basis of schizophrenia. However, how this translates into neurobiological functioning is not clear. Therefore, we aimed to characterize the function of robust susceptibility gene zinc finger protein 804A (ZNF804A), using a model system of relevant cell type and neurodevelopmental timepoint. Based on previous findings, we hypothesized a role for ZNF804A in local protein translation. CRISPR/Cas9-mediated mutation of the risk gene led to increased synapse formation in human induced pluripotent stem cell (hiPSC)-derived developing glutamatergic forebrain neurons as assessed by high-content confocal imaging. Further, mass spectrometry analysis showed an increased recruitment of ribosomes to mutation neurites. Surface sensing of translation (SUnSET) screening complemented this by demonstrating an increased efficiency of local protein synthesis. Overall, these results introduce a novel cellular function for ZNF804A in a model system relevant to schizophrenia, uncovering some aspects of its neurobiology. Ultimately, findings of this study may aid to identify common mechanisms of susceptibility genes.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Maximilian Wulf

LAB HEAD: Deepak P. Srivastava

PROVIDER: PXD047788 | Pride | 2026-03-31

REPOSITORIES: Pride

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Project description:Severe hyposalivation often results from Sjögren’s syndrome or radiation therapy for head and neck cancer. Devastating consequences of hyposalivation, such as rampant dental caries and persistent oral candidiasis, compromise the quality of life in those patients. Clinical management for dry mouth typically involves simple palliative methods or secretagogues, which are designed to stimulate saliva secretion from residual salivary acinar cells present in the glands. However, direct interventions in chronic dryness have yet to be employed in the clinical setting. Despite numerous studies on salivary gland regeneration, the molecular basis governing stem cell transdifferentiation into salivary epithelial precursors (SEP) is largely unknown. Our previously published study clearly indicated mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) can be differentiated into SEP in vitro when co-cultured with isolated primary salivary gland cells without cell-to-cell contact. Our current study utilized iTRAQ-LS-MS/MS-based quantitative proteomics to profile key regulatory factors involved in mouse MSC-to-SEP conversion. We identified 280 differentially expressed proteins in BM-MSCs over the course of 7 days of co-culture. Interestingly, protein expression of salivary transcription factors (STFs), such as transcription factor E2a (TCF3), high mobility group protein 20B (HMG20b), and ankyrin repeat domain-containing protein 56 (ANKRD56) were increased in a time-dependent manner. Notably, pancreas specific transcription factor 1a (PTF1α), muscle, intestine and stomach expression-1 (MIST-1) and achaete-scute complex homolog 3(ASCL3) were newly induced over time in differentiated MSCs. We also identified the expression of Ptf1α in the mouse salivary glands for the first time and verified its expression in independent batches of co-cultured MSCs by western blotting. Furthermore, simulation of the molecular network involving the identified STFs has demonstrated evidence for their perspective roles in salivary gland development during glandular maturation. Thus, our study provides the first extensive proteomic profile of MSC-to-SEP transdifferentiation and identifies novel STFs that may be critical for this process.

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Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

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