Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and after Injury
Temporal Profiling of Astrocyte Precursors Reveals Parallel Roles for Asef during Development and after Injury
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DOI：
10.1523/jneurosci.1658-16.2016
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发表时间：
2016-11-23
影响因子：
5.3
通讯作者：
Deneen, Benjamin
中科院分区：
文献类型：
--
作者：
Chaboub, Lesley S.;Manalo, Jeanne M.;Deneen, Benjamin
谱系发育是一个逐步的过程，受阶段特异性调节因素和相关标记的控制。星形胶质细胞是中枢神经系统的主要细胞类型之一，其发育相关的阶段仍然非常不明确。为了确定这些阶段，我们对脊髓中的星形胶质细胞前体群体进行了基因表达谱分析，确定了其发育过程中与人类星形胶质细胞密切相关的不同基因诱导模式。验证研究确定了发育过程中的一组新的星形胶质细胞相关基因，并证明了它们在人类白质损伤（WMI）中的反应性星形胶质细胞中的表达。对这些基因之一的功能研究表明，缺乏 Asef 的小鼠在 WMI 后的发育和修复过程中表现出星形胶质细胞分化受损，同时成年中枢神经系统中的血脑屏障完整性受损。这些研究已经确定了与人类 WMI 相关的星形胶质细胞谱系发育的不同阶段，并与我们对 Asef 的功能分析一起，强调了星形胶质细胞发育与其与损伤相关的反应性对应物之间的相似之处。
Lineage development is a stepwise process, governed by stage-specific regulatory factors and associated markers. Astrocytes are one of the principle cell types in the CNS and the stages associated with their development remain very poorly defined. To identify these stages, we performed gene-expression profiling on astrocyte precursor populations in the spinal cord, identifying distinct patterns of gene induction during their development that are strongly correlated with human astrocytes. Validation studies identified a new cohort of astrocyte-associated genes during development and demonstrated their expression in reactive astrocytes in human white matter injury (WMI). Functional studies on one of these genes revealed that mice lacking Asef exhibited impaired astrocyte differentiation during development and repair after WMI, coupled with compromised blood-brain barrier integrity in the adult CNS. These studies have identified distinct stages of astrocyte lineage development associated with human WMI and, together with our functional analysis of Asef, highlight the parallels between astrocyte development and their reactive counterparts associated with injury.