Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome.
Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome.
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DOI：
10.1242/dmm.002873
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发表时间：
2012-05
影响因子：
4.3
通讯作者：
Monaghan AP
中科院分区：
文献类型：
--
作者：
Harrison SJ;Nishinakamura R;Jones KR;Monaghan AP
大脑皮层中的祖细胞在发育过程中经历了动态的细胞和分子变化。Sall1是一种被认为在祖细胞发育过程中高度表达的转录因子。在人类中，常染色体显性发育障碍汤恩斯-布罗克斯综合征（TBS）与SALL1基因突变有关。TBS以肾脏、肛门、肢体和听觉异常为特征。虽然神经缺陷尚未被认为是该病的诊断特征，但约10%的患者表现出神经或行为异常。我们证明，除了在外周器官中表达外，Sall1在小鼠中枢神经系统的祖细胞中也有稳定的表达。经典和条件敲除小鼠的研究都表明，大脑皮层对Sall1的缺失特别敏感。在Sall1缺失的情况下，胚胎期第18.5天（E18.5）大脑皮质表面积和深度均下降。这些缺陷与发育过程中祖细胞特性的变化有关。在早期皮质祖细胞中，Sall1促进增殖而非神经原性分裂，而在发育后期，Sall1调节中间祖细胞的产生和分化。此外，Sall1影响皮质层的时间规格。这些发现对发育中的小鼠皮层中Sall1的功能提供了新的见解，并为未来研究TBS患者潜在的神经缺陷提供了途径。
Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ∼10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.
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