Cappuccio Gerarda, Choi William T, Semerci Fatih, Rosenfeld Jill A, Tacorda Toni Claire, Qi Guantong, Zoghbi Anthony W, Zhong Yi, Chen Hu, Liu Pengfei, Liu Zhandong, Maletić-Savatić Mirjana
Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
Stem Cell Reports. 2025 Sep 9;20(9):102606. doi: 10.1016/j.stemcr.2025.102606. Epub 2025 Aug 21.
Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause Mendelian neurological conditions. In addition, leveraging a variety of computational tools and clinical and population databases, we identified 15 genes bearing novel damaging variants linked to neurological phenotypes, suggesting their potential role in contributing to human phenotypes. These discoveries illuminate NPC molecular underpinnings and underscore their relevance to both brain development and disease.
成体海马神经发生，即产生新神经元的过程，依赖于齿状回复合微环境中一类罕见的神经干细胞和祖细胞（NPCs）。由于表达模式重叠，利用传统方法难以检测到罕见细胞群体，因此发现定义这些细胞的特定基因至关重要但具有挑战性。通过采用基于模式识别对复杂基因表达数据进行反卷积的计算数字分选算法（DSA），我们鉴定出129个在小鼠NPCs中富集的基因。我们根据已发表的单细胞RNA测序（scRNA-seq）数据验证了这些基因，发现其中25个人类直系同源基因已知会导致孟德尔神经疾病。此外，利用各种计算工具以及临床和群体数据库，我们鉴定出15个携带与神经表型相关的新型有害变异的基因，表明它们在导致人类表型方面的潜在作用。这些发现阐明了NPCs的分子基础，并强调了它们与大脑发育和疾病的相关性。
