Generation of a mouse model of the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome.
Gerardo ZapataKeqin YanDavid J PickettsPublished in: Human molecular genetics (2022)
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.
Keyphrases
- transcription factor
- genome wide identification
- intellectual disability
- cell death
- dna binding
- amino acid
- case report
- mouse model
- high fat diet induced
- autism spectrum disorder
- spinal cord
- genome wide
- end stage renal disease
- newly diagnosed
- gene expression
- poor prognosis
- peritoneal dialysis
- copy number
- minimally invasive
- oxidative stress
- magnetic resonance
- metabolic syndrome
- risk factors
- chronic kidney disease
- zika virus
- patient reported outcomes
- wild type
- signaling pathway
- mesenchymal stem cells
- cell proliferation
- cerebral ischemia
- subarachnoid hemorrhage
- congenital heart disease
- gestational age
- early life
- data analysis