2012年9月24日 電 /生物谷BIOON/ --近日,，冷春港實(shí)驗(yàn)室（CSHL）研究人員已經(jīng)解決了一個(gè)重要的神經(jīng)科學(xué)難題：哺乳動(dòng)物大腦中的祖細(xì)胞是如何在復(fù)制自己的同時(shí)也生成神經(jīng)元的,。
驗(yàn)室教授Van Aels博士和他的同事著手研究視網(wǎng)膜神經(jīng)節(jié)細(xì)胞以及錐體神經(jīng)元的祖細(xì)胞--放射性狀膠質(zhì)細(xì)胞,，放射性狀膠質(zhì)細(xì)胞是成熟哺乳動(dòng)物大腦皮質(zhì)興奮性神經(jīng)細(xì)胞類型中最常見的類型,。
利用轉(zhuǎn)基因操作小鼠，Van Aelst團(tuán)隊(duì)證明,，一個(gè)稱為DOCK7的蛋白質(zhì)在決定放射性狀膠質(zhì)細(xì)胞如何以及何時(shí)“決定”是增殖生成更多的祖細(xì)胞,，還是分化成錐體神經(jīng)元過程中扮演一個(gè)中央調(diào)控。研究結(jié)果發(fā)表在2012年9月號(hào)的Nature Neuroscience雜志上,。
DOCK7已知在嚙齒動(dòng)物腦的各部分包括海馬和皮層中高表達(dá),。它已被Van Aelst和同事證明能控制連接神經(jīng)元軸突的形成。在其新發(fā)表的研究,， Van Aelst博士和Yu-Ting Yang,、Chia-Lin Wang研究生研究人員闡明了DOCK7是如何交替沉默和過表達(dá)調(diào)節(jié)蛋白質(zhì)的。
當(dāng)小鼠沉默胚胎蛋白質(zhì)后,，神經(jīng)細(xì)胞的分化受阻，視網(wǎng)膜神經(jīng)節(jié)細(xì)胞保持其祖狀態(tài),。而當(dāng)DOCK7過度表達(dá)時(shí),，視網(wǎng)膜神經(jīng)節(jié)細(xì)胞分化過早，導(dǎo)致生成更多的神經(jīng)元,，視網(wǎng)膜神經(jīng)節(jié)細(xì)胞減少,。
除了闡明DOCK7對(duì)皮質(zhì)發(fā)育的重要作用機(jī)制外，新的研究還揭示了頭小畸型癥發(fā)病機(jī)制,，頭小畸型癥的特點(diǎn)是不正常的大腦體積以及神經(jīng)發(fā)育障礙如精神分裂癥等,。如果DOCK7表達(dá)是不正常的，DOCK7會(huì)擾亂正常的神經(jīng)發(fā)生,。在今后的研究工作中,，研究人員希望探索DOCK7畸變引起的神經(jīng)生成是否會(huì)導(dǎo)致皮質(zhì)電路不平衡，造成各種病理疾病,。
這項(xiàng)工作得到了美國國立健康項(xiàng)目MH082808,、紐約STARR財(cái)團(tuán)以及美國國家衛(wèi)生研究院等資助。
doi:10.1038/nn.3171
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DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis
Yu-Ting Yang,Chia-Lin Wang& Linda Van Aelst
Neurogenesis in the developing neocortex relies on the ability of radial glial progenitor cells (RGCs) to switch from proliferative to differentiative neuron-generating divisions, but the molecular mechanisms that control this switch in a correct temporal manner are not well understood. Here, we show that DOCK7, a member of the DOCK180 family of proteins, regulates RGC proliferation versus differentiation. Silencing of DOCK7 in RGCs of developing mouse embryos impedes neuronal differentiation and maintains cells as cycling progenitors. In contrast, DOCK7 overexpression promotes RGC differentiation to basal progenitors and neurons. We further present evidence that DOCK7 influences neurogenesis by controlling apically directed interkinetic nuclear migration of RGCs. DOCK7 exerts its effects by antagonizing the microtubule growth-promoting function of the centrosome-associated protein TACC3. Thus, DOCK7 interaction with TACC3 controls interkinetic nuclear migration and the genesis of neurons from RGCs during cortical development
