The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb1^{1148del/1148del} mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes.

BAF（BRG1/BRM 相关因子）染色质重塑复合物对于神经元分化过程中 DNA 可及性和基因表达的调节至关重要。其核心亚基SMARCB1的突变会导致多种病理，包括侵袭性横纹肌样瘤或神经发育障碍。其他小鼠模型已经解决了Smarcb1纯合或杂合缺失的影响，但特定非截短突变的影响仍然知之甚少。在这里，我们针对羧基末端Smarcb1 c.1148del 点突变建立了一个新的小鼠模型，该突变导致了延长的 SMARCB1 蛋白的合成。我们利用磁共振成像、组织学和单细胞 RNA 测序研究了它对小鼠大脑发育的影响。在青春期，Smarcb1 ^{1148del/1148del}小鼠体重增加相当缓慢，并且经常出现脑积水，包括侧脑室扩大。在胚胎和新生儿阶段，突变大脑在解剖学和组织学上与野生型对照没有差异。对新生突变小鼠大脑的单细胞 RNA 测序表明，尽管存在 SMARCB1 突变，但仍形成了包含生理小鼠大脑所有细胞类型的完整大脑。然而，新生小鼠的神经信号传导似乎受到干扰，因为 AP-1 转录因子家族的基因和神经突生长相关的转录本被下调。这些发现支持 SMARCB1 在神经发育中的重要作用，并扩展了对不同Smarcb1突变及其相关表型的认识。