SEC14 and spectrin domains-1 (SESTD1) 蛋白在腦部中具有高度的表現。研究發現，全身性去除SESTD1的小鼠 (Sestd1 knockout mice) 會表現出胚胎發育不全、短尾、生殖器異常、無肛門、腎積水、無膀胱及脊柱裂等病理特徵。我們實驗室先前發現SESTD1具有負向調控Rac1-Trio8訊息傳遞路徑，進而減少樹突棘突 (dendritic spine) 及減少海馬迴神經細胞興奮性神經突觸傳遞的作用。在本研究中，我們擬探討SESTD1在胚胎神經幹細胞增生及分化過程中所扮演的角色。我們主要的發現為在胚胎神經幹細胞發育的過程中，SESTD1會表現於神經幹細胞、前驅細胞、未成熟神經細胞以及成熟神經細胞中，顯示SESTD1參與於神經細胞發育過程中。在功能上，將Sestd過度表現會降低胚胎神經幹細胞的增生作用，反之，將Sestd1剔除，神經幹細胞的增生作用會被加強。此外，利用流式細胞儀觀察發現，Sestd1過度表現會造成神經幹細胞停滯於G0/G1時期；反之，將Sestd1剔除會促使神經幹細胞離開G0/G1時期進入S時期。另外，利用TUNEL方法檢測，不管是增加或減少SESTD1的表現，都不會影響細胞凋亡。我們更進一步確定，SESTD1可以藉由抑制Rac1活性，進而利用AKT/GSK3β/β-catenin/cyclin D1訊息傳遞路徑，促使神經幹細胞無法正常進行G1/S轉移 (G1/S phase transition)。這些結果都顯示，SESTD1具有負向調控Rac1訊號路徑的作用，進而抑制神經幹細胞的增生作用。此外，在成年小鼠海馬迴齒狀迴 (dentate gyrus) 中，將新生神經細胞的Sestd1分別進行過度表現及剔除處理後的二週及四週進行觀察發現，Sestd1的過度表現或剔除並不會影響新生神經細胞的座落位置 (location) 和細胞本體的大小 (soma size)。在二週時，樹突長度 (length) 和分支數目 (branch number) 也不會因為Sestd1的過度表現或剔除而有所影響；但在四週時，在Sestd1過度表現組別觀察到，樹突的長度以及分支數目則有明顯降低的現象。利用Sholl analysis分析SESTD1改變對新生神經細胞的結構以及型態影響，在二週時，Sestd1過度表現或剔除組別的神經突觸複雜度 (complexity) 均和控制組沒有差異；而在四週時，Sestd1過度表現組別的神經突觸複雜程度明顯降低，而Sestd1剔除組別則沒有和控制組有所差異。本研究結果對於SESTD1在生物體內的功能提供更深入的瞭解，發現SESTD1不僅抑制神經幹細胞的增生作用，在腦中SESTD1對於海馬迴新生神經細胞的結構塑性上也扮演著相當重要的調控角色。
中文關鍵字：SESTD1、胚胎神經幹細胞、增生作用、分化作用、細胞週期、Rac1、樹突結構型態

SESTD1 is highly expressed in the brain. Our previous studies have identified that SESTD1 may act as a negative regulator of the Rac1-Trio8 signaling pathway to reduce dendritic spine density and lower excitatory synaptic transmission in hippocampal neurons. In this study, we plan to delineate the role of SESTD1 in regulating the proliferation and differentiation of fetal neural stem cells (NSCs). Here, we show that SESTD1 colocalizes with radial glial cell marker glial fibrillary acidic protein (GFAP), progenitor marker nestin, and neuroblast and immature neuronal marker doublecortin in the dentate gyrus of adult mouse hippocampus and fetal hippocampal NSCs. Overexpression of SESTD1 decreases proliferation of fetal NSCs detected by bromodeoxyuridine (BrdU) incorporation and neurosphere formation assay. Conversely, knockdown of SESTD1 increases the number BrdU-labeled cells and produces more neurospheres with larger sizes. Further analysis by the Flow cytometry assay revealed that overexpression of SESTD1 increases cell cycle exit and decreases cell cycle re-entry. Overexpression of SESTD1 induces G0/G1 phase arrest, whereas knockdown of SESTD1 decreases the percentage of cells in G0/G1 phase and increases the percentage of cells in G1/S phase transition. Overexpression or knockdown of SESTD1 exhibits no effect on NSC apoptosis using the apoptotic assay. Moreover, we confirm that SESTD1 participates in AKT/GSK3/cyclin D1 signaling pathway to regulate G1/S phase transition by suppressing Rac1 activity. Finally, we find that overexpression of SESTD1 may alter neural stem cell differentiation in the dentate gyrus of adult mouse hippocampus using retrovirus-mediated cell labeling strategy to precisely birthdate newborn dentate granule cells. These results suggest that SESTD1 may act as a negative regulator of the Rac1 signaling pathway to regulate NSC proliferation and differentiation.

Keywords: SESTD1, embryonic neural stem cell, proliferation, differentiation, cell cycle, Rac1, structural morphology

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