線蟲Wnt Signaling調控不對稱分裂與細胞分化

Abstract

不對稱細胞分裂可以增加細胞的多樣性，對擁有許多不同種類細胞的神經系統來說至關重要。Wnt-Frizzled 訊息路徑是調控不對稱細胞分裂的重要因子。在線蟲中，V5 側縫細胞系會產生，身體兩側各一個PVD痛覺神經細胞，而lin-17/Frizzled 突變造成PVD數目異常增加。我們的研究顯示，lin-17 和Wnt基因的突變導致V5.pa母細胞產生對稱而非不對稱的分裂，進而使神經膠質母細胞被轉化成神經母細胞。我們發現許多 Wnt 訊息傳遞路徑的基因都影響PVD的分化，而Wnt 訊號的分布方向能引導細胞不對稱分裂的極性。我們發現控制真皮細胞和神經膠細胞分化的C2H2轉錄因子LIN-26，其在神經膠母細胞中的表現量在lin-17突變株中明顯減少。利用RNA干擾技術，我們發現 lin-26和同屬於lin-26操縱子的另一類似基因lir-1在決定V5.pa細胞系性狀分化上的重要性，尤其lin-17突變的狀態下，失去lin-26或lir-1都會產生更多PVD神經細胞。除此之外，lin-17與mom-5/Frizzled同時突變時，側縫細胞大量消失且造成極度異常的PVD數目。這個結果表示Frizzled在調控不對稱細胞分裂中的重要性，並證明其透過影響lin-26/lir-1操縱子的表現而引導神經膠細胞與外皮層細胞的分化，以防止神經細胞異常的產生。

Wnt-Frizzled signaling is an important regulator of asymmetric cell division that increases cellular diversity. In the nematode Caenorhabditis elegans, mutations in lin-17/Frizzled resulted in supernumerary PVDs, one of the two postdeirid neurons generated by the V5 seam cell lineage. The asymmetric division of the V5.pa, which generated the neuroblast and the glioblast of the postdeirid, was often disrupted in the lin-17 and Wnt mutants. We identified multiple Wnt pathway genes that controlled PVD specification, and showed that Wnts instructed the asymmetry of cell division. Interestingly, expression of lin-26, a C2H2 transcription factor critical for hypodermal and glial cell specification, was significantly diminished in the postdeirid glial lineage of the lin-17 mutant. Reduced activity of lin-26 or lir-1, a lin-26-like gene encoded by the lir-1/lin-26 operon, resulted in supernumerary PVDs and enhanced lin-17 mutant phenotypes. Moreover, combining mutations of lin-17 and another Frizzled, mom-5, resulted in substantial loss of seam cells and extremely aberrant PVD numbers. These results support a model in which Frizzled couples asymmetric cell division to a switch in lin-26/lir-1 transcriptional activity to promote glial or epidermal fates against an otherwise differentiation program towards neurons.