Generation of a mouse model of the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome
| العنوان: | Generation of a mouse model of the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome |
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| المؤلفون: | Gerardo Zapata, Keqin Yan, David J Picketts |
| المصدر: | Hum Mol Genet |
| بيانات النشر: | Oxford University Press (OUP), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Mice, Knockout, Sucrose, Facies, Antigens, Nuclear, Nerve Tissue Proteins, Syndrome, General Medicine, Chromatin Assembly and Disassembly, Actins, Chromatin, Nucleosomes, Mice, Neurodevelopmental Disorders, Basic Helix-Loop-Helix Transcription Factors, Genetics, Animals, Original Article, Amino Acids, Molecular Biology, Genetics (clinical), Transcription Factors |
| الوصف: | Heterozygous variants in bromodomain and plant homeodomain containing transcription factor (BPTF) cause the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) syndrome (MIM#617755) characterized by intellectual disability, speech delay and postnatal microcephaly. BPTF functions within nucleosome and remodeling factor (NURF), a complex comprising sucrose non-fermenting like (SNF2L), an Imitation SWItching (ISWI) chromatin remodeling protein encoded by the SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1 (SMARCA1) gene. Surprisingly, ablation of Smarca1 resulted in mice with enlarged brains, a direct contrast to the phenotype of NEDDFL patients. To model the NEDDFL syndrome, we generated forebrain-specific Bptf knockout (Bptf conditional Knockout (cKO)) mice. The Bptf cKO mice were born in normal Mendelian ratios, survived to adulthood but were smaller in size with severe cortical hypoplasia. Prolonged progenitor cell cycle length and a high incidence of cell death reduced the neuronal output. Cortical lamination was also disrupted with reduced proportions of deep layer neurons, and neuronal maturation defects that impaired the acquisition of distinct cell fates (e.g. COUP-TF-interacting protein 2 (Ctip2)+ neurons). RNAseq and pathway analysis identified altered expression of fate-determining transcription factors and the biological pathways involved in neural development, apoptotic signaling and amino acid biosynthesis. Dysregulated genes were enriched for MYC Proto-Oncogene, BHLH Transcription Factor (Myc)-binding sites, a known BPTF transcriptional cofactor. We propose the Bptf cKO mouse as a valuable model for further study of the NEDDFL syndrome. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::95039255004c90f41c0c9e60a963d8d4Test https://doi.org/10.1093/hmg/ddac119Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....95039255004c90f41c0c9e60a963d8d4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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