Center for Medical Science, International University of Health and Welfare, Otawara, Tochigi, Japan.
J Neurochem. 2012 Jul;122(1):72-80. doi: 10.1111/j.1471-4159.2011.07524.x. Epub 2011 Nov 3.
FOXP2, a forkhead box-containing transcription factor, forms homo- or hetero-dimers with FOXP family members and localizes to the nucleus, while FOXP2(R553H), which contains a mutation related to speech/language disorders, features reduced DNA binding activity and both cytoplasmic and nuclear localization. In addition to being a loss-of-function mutation, it is possible that FOXP2(R553H) also may act as a gain-of-function mutation to inhibit the functions of FOXP2 isoforms including FOXP2Ex10+ lacking forkhead domain. Foxp2(R552H) knock-in mouse pups exhibit impaired ultrasonic vocalization and poor dendritic development in Purkinje cells. However, expressions of Foxp2 isoforms in the developing Purkinje are unclear. The appearance of 'apical cytoplasmic swelling' (mitochondria-rich regions that are the source of budding processes) correlates with dendritic development of Purkinje cells. In the present study, we focused on Foxp2 isoforms localizing to the apical cytoplasmic swelling and identified two isoforms lacking forkhead domain: Foxp2Ex12+ and Foxp2Ex15. They partly localized to the membrane fraction that includes mitochondria. Foxp2Ex12+ mainly localized to the apical cytoplasmic swelling in early developing Purkinje cells at the stellate stage (P2-P4). Mitochondrial localization of Foxp2Ex12+ in Purkinje cells was confirmed by immune-electron microscopic analysis. Foxp2Ex12+ may play a role in dendritic development in Purkinje cells.
叉头框蛋白 2（FOXP2）是一种包含叉头框的转录因子，它与 FOXP 家族成员形成同源或异源二聚体，并定位于细胞核内，而含有与言语/语言障碍相关突变的 FOXP2（R553H）则表现出降低的 DNA 结合活性以及细胞质和核定位。除了是功能丧失性突变之外，FOXP2（R553H）也可能作为功能获得性突变，抑制包括缺失叉头结构域的 FOXP2Ex10+在内的 FOXP2 同工型的功能。Foxp2（R552H）敲入小鼠幼仔表现出超声发声受损和浦肯野细胞树突发育不良。然而，发育中的浦肯野细胞中 Foxp2 同工型的表达尚不清楚。“顶端细胞质肿胀”（富含线粒体的区域，是出芽过程的来源）的出现与浦肯野细胞树突的发育相关。在本研究中，我们专注于定位于顶端细胞质肿胀的 Foxp2 同工型，并鉴定出两种缺失叉头结构域的同工型：Foxp2Ex12+和 Foxp2Ex15。它们部分定位于包含线粒体的膜部分。Foxp2Ex12+主要定位于星状阶段（P2-P4）的早期发育中的浦肯野细胞的顶端细胞质肿胀中。通过免疫电子显微镜分析证实了 Foxp2Ex12+在浦肯野细胞中的线粒体定位。Foxp2Ex12+可能在浦肯野细胞的树突发育中发挥作用。
