FoxP2在胚胎時期的神經新生中所扮演的角色

Abstract

目前已知FoxP2為一轉錄因子，在人類中如產生突變，會影響語言的能力。此外，在斑胸草雀有一個學習唱歌的神經迴路Area X，降低Area X的FoxP2 的表現量，會使之無法學會該物種鳴叫的旋律和降低中度棘神經元的發育。以小鼠為例，剔除FoxP2會使小鼠的動作學習產生缺失。這些都暗示著FoxP2可能會調控神經元新生，但FoxP2影響神經元新生的機制尚未明確。因此本論文要探討在神經系統的發育過程中，FoxP2所扮演的角色為何。將胚胎鼠前腦的細胞進行初級細胞培養，我發現FoxP2會增加神經元分化和突觸的長度而不會去影響細胞增生及細胞死亡。另外，我也發現FoxP2會增加PDGFRα的表現量且FoxP2所影響的神經元分化是透過PDGFRα。在前腦腹側神經元特化的部分，我發現FoxP2對於中度棘神經元的分化是必須的，且FoxP2會抑制中間神經元的分化。根據日前研究指出FoxP2和另一已知調控前腦中間神經元的轉錄因子Nkx2-1有交互作用。我也發現維持Nkx2-1 表現的Sonic hedgehog pathway會影響FoxP2調控神經元類型的特化。由以上結果可知FoxP2在調控胚胎時期前腦的神經元特化過程中扮演重要的角色。

In humans, mutations of FoxP2, a transcription factor, cause a severe speech and language disorder. In addition, reduction of FoxP2 expression in the basal ganglia song nucleus Area X in zebra finches causes deficits in song learning and the development of medium spiny neurons. In mouse models, loss-of-function of FoxP2 causes defects in motor learning. These suggest that FoxP2 plays important roles during neural development. However, the mechanism is still unclear. Therefore, the present study is aimed to investigate effects of FoxP2 during the development of the nervous system. By using primary cell cultures from the embryonic telencephalon, I observed that FoxP2 increased neuronal differentiation and neurite length without affecting cell proliferation and cell survival. I also found that FoxP2 increased the expression of platelet-derived growth factor receptor α (PDGFRα) and the neurognic effect of FoxP2 was PDGFRα-dependent. In terms of neuronal subtype specification, I found that FoxP2 positively regulated the differentiation of lateral ganglionic eminence (LGE)-derived medium spiny neurons and negatively regulated the formation of medial ganglionic eminence (MGE)-derived interneurons. Since previous studies showed that there was interaction between FoxP2 and Nkx2-1, a transcription factor known for the development of the forebrain interneurons, I found that the effect of FoxP2 on the differentiation of forebrain interneurons was mediated by the Sonic hedgehog pathway, which maintains Nkx2-1 expression and the specification of interneurons. Taken together, my study suggests that FoxP2 regulates the development of the embryonic forebrain.