LAUSR

Heterozygous variants in BPTF cause the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) syndrome (MIM#617755) characterized by intellectual disability (ID), speech delay, and postnatal microcephaly. BPTF functions within NURF, a complex comprising SNF2L, an ISWI chromatin remodeling protein encoded by the 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 cKO) mice. 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 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 (eg. Ctip2+ neurons). RNAseq and pathway analysis identified altered expression of fate-determining transcription factors, and biological pathways involved in neural development, apoptotic signaling, and amino acid biosynthesis. Dysregulated genes were enriched for Myc binding sites, a known BPTF transcriptional co-factor. We propose Bptf cKO mice as a valuable model for further study of the NEDDFL syndrome.