Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany.
PLoS Genet. 2021 Mar 19;17(3):e1009441. doi: 10.1371/journal.pgen.1009441. eCollection 2021 Mar.
Biallelic mutations in DONSON, an essential gene encoding for a replication fork protection factor, were linked to skeletal abnormalities and microcephaly. To better understand DONSON function in corticogenesis, we characterized Donson expression and consequences of conditional Donson deletion in the mouse telencephalon. Donson was widely expressed in the proliferation and differentiation zones of the embryonic dorsal and ventral telencephalon, which was followed by a postnatal expression decrease. Emx1-Cre-mediated Donson deletion in progenitors of cortical glutamatergic neurons caused extensive apoptosis in the early dorsomedial neuroepithelium, thus preventing formation of the neocortex and hippocampus. At the place of the missing lateral neocortex, these mutants exhibited a dorsal extension of an early-generated paleocortex. Targeting cortical neurons at the intermediate progenitor stage using Tbr2-Cre evoked no apparent malformations, whereas Nkx2.1-Cre-mediated Donson deletion in subpallial progenitors ablated 75% of Nkx2.1-derived cortical GABAergic neurons. Thus, the early telencephalic neuroepithelium depends critically on Donson function. Our findings help explain why the neocortex is most severely affected in individuals with DONSON mutations and suggest that DONSON-dependent microcephaly might be associated with so far unrecognized defects in cortical GABAergic neurons. Targeting Donson using an appropriate recombinase is proposed as a feasible strategy to ablate proliferating and nascent cells in experimental research.
双等位基因突变 Donson，一个编码复制叉保护因子的必需基因，与骨骼异常和小头症有关。为了更好地理解 Donson 在皮质发生中的功能，我们对 Donson 在小鼠端脑中的表达和条件性 Donson 缺失的后果进行了表征。Donson 在胚胎背侧和腹侧端脑的增殖和分化区广泛表达，随后在出生后表达减少。Emx1-Cre 介导的皮质谷氨酸能神经元祖细胞中的 Donson 缺失导致早期背内侧神经上皮广泛凋亡，从而阻止新皮质和海马体的形成。在缺失的外侧新皮质部位，这些突变体表现出早期生成的古皮质的背侧延伸。使用 Tbr2-Cre 靶向中间祖细胞阶段的皮质神经元不会引起明显的畸形，而 Nkx2.1-Cre 介导的 subpallial 祖细胞中的 Donson 缺失则消除了 75%的 Nkx2.1 衍生的皮质 GABA 能神经元。因此，早期端脑神经上皮对 Donson 功能的依赖至关重要。我们的研究结果有助于解释为什么 DONSON 突变个体的新皮质受影响最严重，并表明 DONSON 依赖性小头症可能与皮质 GABA 能神经元的未被识别的缺陷有关。使用适当的重组酶靶向 Donson 被提议作为一种可行的策略，以在实验研究中消除增殖和新生细胞。
