Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development
Differential expression of paralog RNA binding proteins establishes a dynamic splicing program required for normal cerebral cortex development
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DOI：
10.1093/nar/gkae071
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发表时间：
2024-02-07
影响因子：
14.9
通讯作者：
Sette，Claudio
中科院分区：
文献类型：
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作者：
Cesari，Eleonora;Farini，Donatella;Sette，Claudio
Sam68和SLM2是在大脑皮层表达的类似RNA结合蛋白（rbp），具有相似的剪接活性。然而，它们在皮层发育过程中的相关功能尚不清楚。我们发现这些rbp在发育过程中表现出相反的表达模式。Sam68的表达在出生后下降，而SLM2的表达在出生后增加，并且这种发育模式通过SLM2对Sam68表达的分层控制而得到加强。对Sam68: slm2双敲除（Sam68:Slm2dko）小鼠的分析揭示了数百个外显子对这些蛋白质的联合消耗做出反应。此外，单敲除和双敲除皮质的平行分析表明，主要受SLM2调控的外显子在发育过程中具有动态剪接模式，而依赖sam68的外显子则以相对恒定的速率剪接。slm2敏感外显子的动态剪接在sam68: slm2dko发育的皮层中被完全抑制。Sam68:Slm2dkomice在围产期死亡时伴有神经发生和神经元分化缺陷，并发展为脑积水，与这些生物过程相关的基因剪接改变一致。因此，我们的研究表明，编码同源rbp的分离esam68和slm2平行基因的发育控制能够协调大脑发育和生存所需的动态剪接程序，同时确保支持适当皮层发育的稳健冗余机制。
Sam68 and SLM2 are paralog RNA binding proteins (RBPs) expressed in the cerebral cortex and display similar splicing activities. However, their relative functions during cortical development are unknown. We found that these RBPs exhibit an opposite expression pattern during development. Sam68 expression declines postnatally while SLM2 increases after birth, and this developmental pattern is reinforced by hierarchical control of Sam68 expression by SLM2. Analysis ofSam68:Slm2double knockout (Sam68:Slm2dko) mice revealed hundreds of exons that respond to joint depletion of these proteins. Moreover, parallel analysis of single and double knockout cortices indicated that exons regulated mainly by SLM2 are characterized by a dynamic splicing pattern during development, whereas Sam68-dependent exons are spliced at relatively constant rates. Dynamic splicing of SLM2-sensitive exons is completely suppressed in theSam68:Slm2dkodeveloping cortex.Sam68:Slm2dkomice die perinatally with defects in neurogenesis and in neuronal differentiation, and develop a hydrocephalus, consistent with splicing alterations in genes related to these biological processes. Thus, our study reveals that developmental control of separateSam68andSlm2paralog genes encoding homologous RBPs enables the orchestration of a dynamic splicing program needed for brain development and viability, while ensuring a robust redundant mechanism that supports proper cortical development.