Ortiz Ana, Ayhan Fatma, Khandelwal Nitin, Outland Elliot, Jankovic Miranda, Harper Matthew, Konopka Genevieve
Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
Cell Rep. 2025 Mar 25;44(3):115384. doi: 10.1016/j.celrep.2025.115384. Epub 2025 Mar 5.
Forkhead box protein P1 (FOXP1), a transcription factor enriched in the neocortex, is associated with autism spectrum disorders (ASDs) and FOXP1 syndrome. Emx1;Foxp1 conditional deletion (Foxp1 conditional knockout [cKO]) in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell-type-specific mechanisms underlying these changes remained unclear. We find that Foxp1 deletion results in accelerated pseudo-age during early neurogenesis, increased cell cycle exit during late neurogenesis, altered gene expression and chromatin accessibility, and selective migration deficits in a subset of upper-layer neurons. These data explain the postnatal differences observed in cortical layers and relative cortical thickness. We also highlight genes regulated by FOXP1 and their enrichment with high-confidence ASD or synaptic genes. Together, these results underscore a network of neurodevelopmental-disorder-related genes that may serve as potential modulatory targets for postnatal modification relevant to ASDs and FOXP1 syndrome.
叉头框蛋白P1（FOXP1）是一种在新皮层中富集的转录因子，与自闭症谱系障碍（ASD）和FOXP1综合征相关。小鼠皮层中的Emx1;Foxp1条件性缺失（Foxp1条件性敲除[cKO]）会导致皮层整体厚度降低、皮质分层改变以及皮质层相对厚度变化。然而，这些变化背后的发育和细胞类型特异性机制仍不清楚。我们发现，Foxp1缺失导致早期神经发生过程中假年龄加速、晚期神经发生过程中细胞周期退出增加、基因表达和染色质可及性改变，以及上层神经元亚群中的选择性迁移缺陷。这些数据解释了在皮质层和相对皮质厚度中观察到的出生后差异。我们还强调了受FOXP1调控的基因及其与高可信度ASD或突触基因的富集情况。总之，这些结果强调了一个与神经发育障碍相关的基因网络，该网络可能作为与ASD和FOXP1综合征相关的出生后修饰的潜在调节靶点。
