Fig. 8: Variations in cortical growth caused by ablation of different NURF components.
A Image showing size differences of brains (P20) dissected from different NURF mutant genotypes or their control littermates (WT). Numbers correspond to the cortical area ratio between the mutant and WT animals (n = 2). Ex6DEL refers to the Smarca1ex6del line. cKO, conditional knockout; dKO, double conditional knockout. B P10 cerebellar extracts isolated from control (WT) or Smarca1 KO animals immunoblotted for SMARCA1, SMARCA5, and CECR2. C) Co-immunoprecipitation assays performed from WT (upper panels) or Smarca1 KO (lower panels) cerebellar extracts with antibodies to SMARCA5 or rabbit IgG. 5% of the total IP lysate was loaded as input. Experiments in B and C were repeated two additional times using lysates prepared from different animals. Source data are provided as a Source Data file. D Model of NURF complex subunit switching. (i) The NURF complex is expressed in proliferating neuroprogenitors (NPCs) and in differentiated neurons during murine corticogenesis. (ii) During normal cortical development (WT), the catalytic subunit of NURF is SMARCA5 during growth which is switched to SMARCA1 during differentiation. (iii) Ablation of the Bptf gene (Bptf cKO) prevents formation of the NURF complex and results in minimal growth and a severely hypoplastic cortex. Individuals with BPTF pathogenic variants also present with microcephaly. (iv) When Smarca5 is inactivated (Smarca5 cKO), there is some compensation by SMARCA1 during growth that results in reduced cortical volume but a slightly larger cortex than the Bptf cKO mice. Individuals with SMARCA5 variants also present with microcephaly. (v) Smarca1 KO mice have a normal sized cortex which results from near complete compensation by the SMARCA5 protein. (vi) In the Smarca1ex6del mice, subunit switching occurs normally but the mutant protein lacks remodeling activity creating a dominant negative effect that delays differentiation and results in a larger brain size. Individuals with SMARCA1 variants and macrocephaly are predicted to lack remodeling activity and function in a dominant negative fashion, while variants not associated with macrocephaly are predicted to be functional hypomorphs.
