低氧誘導因子 (Hif1α ) 經 Atx-Lpar3 訊息傳導路徑 調控斑馬魚心臟發育

Abstract

低氧環境可以誘發許多訊息傳導進而影響細胞內的功能表現,其 中對於此狀態促進生成低氧誘導因子調控血管新生和細胞爬行等多項 細胞表現研究,早已被廣泛所知。低氧誘導因子有分成不同型,其中 的 α 型在基因惕除鼠的實驗下,證實 Hif1α 的缺失會導致心臟發育的不 全,容易有心二分支的現象出現,更嚴重發育的即是死亡。有趣的是 在斑馬魚胚藉由顯微注射水解磷脂酸受器 3 (lpar3) 反義吗啉寡聚核苷 酸(morpholino oligonucleotides, MO)中,亦發現了心二分支的現象。 不但如此,水解磷脂酸 (LPA) 和低氧誘導因子之間的相連性也早有許 多相關研究。 因此對於低氧誘導因子是否有調節水解磷脂酸經由其酵素水解磷 脂酸合成脢 (Ha, Perez-Iratxeta et al.) 切割及其受器-水解磷脂酸受器 3 的訊息傳導路徑深感興趣。在利用反義吗啉寡聚核苷酸降低低氧誘導 因子的表現量去觀察心血管的發育過程。在進行一連串相關的實驗 後,都證明低氧誘導因子 α 型的缺失會造成心臟前驅細胞早期的爬行 異常,進而造成其發育方向的異位。同時,進一步的探討低氧誘導因 子對於 Kupffer’s vesicle 的影響。因此我認為低氧誘導因子在斑馬魚胚 胎對心臟形成及發育過程和左右不對稱性有著重要的影響。

Hypoxia is known to regulate gene expression via hypoxia- inducible factors (HIFs) and plays a role in many developmental processes, including vasculogenesis, angiogenesis, heart and central nervous system development. The Hif1α knockout mice shows defective heart development, including cardia bifida and abnormal neural crest migration. Recently, we have observed heart left-right asymmetric defects and cardia bifida in zebrafish embryos deficient in lysophosphatidic acid (LPA) synthesizing enzyme autotoxin and on of its receptors, LPAR3. LPA signaling stimulates cell proliferation, cell migration, survival of many cell types, tumorigenesis, angiogenesis, and metastasis. More interestingly, hypoxia is known to enhance LPA- induced Hif1α expression. Therefore, I hypothesize that Hif1α may regulate heart development through the Atx-Lpar3 pathway. Thus, I tested the idea that LPA may interact with HIF signaling to mediate cardiogenesis. Using the MO knockdown approach, I demonstrate that Hif1α and Lpar3 reciprocally regulate each other’s gene expression and rescues respective cardiac defects. Also, I investigate the connection between Hif1α and Atx. These results suggest that Hif1α, Atx and Lpar3 work together to mediate cardiac development.