Restriction on self-renewing asymmetric division is coupled to terminal asymmetric division in the Drosophila CNS.
Restriction on self-renewing asymmetric division is coupled to terminal asymmetric division in the Drosophila CNS.
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DOI：
10.1371/journal.pgen.1009011
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发表时间：
2020-09
期刊：
影响因子：
4.5
通讯作者：
Bhat KM
中科院分区：
文献类型：
--
作者：
Gaziova I;Gazi M;Mar J;Bhat KM
神经元前体细胞经过自我更新和非自我更新的不对称分裂，产生大量不同身份的神经元。在果蝇中，初级前体细胞神经母细胞经历了不同数量的自我更新的不对称分裂，有一个已知的例外，MP2谱系，它只经历了一次类似于次级前体细胞的终端不对称分裂。调控从自我更新到非自我更新的不对称分裂或前体分裂次数转变的机制和基因尚不清楚。在这里，我们展示了T-box转录因子Midline (Mid)，耦合了这些事件。我们发现，在功能突变的中期丧失中，MP2经历了额外的自我更新的不对称分裂，后代神经元的身份依赖于母体MP2的麻木定位。MP2对Mid的表达是短暂的，在MP2中过表达可阻断其分裂。调控MP2在mid中自我更新的不对称分裂的机制涉及Cyclin E的上调。我们的研究结果表明，mid通过结合Cyclin E启动子中一个变异的mid结合位点来抑制Cyclin E基因的表达，并抑制其表达，而不是完全消除它。与此一致的是，cyclin E在MP2中的过度表达导致其多次自我更新的不对称分裂。这些结果揭示了一种通过抑制细胞周期蛋白E来限制细胞自我更新的不对称分裂潜能并促进其退出细胞周期的中调控途径。所有生物体的大脑、脊髓、肠道等神经细胞都是由干细胞产生的。这些原代细胞分裂自我更新，同时产生一个次级前体细胞，最终分裂产生两个细胞，分化成不同身份的神经元，或胶质细胞，或神经元和胶质细胞。次级细胞从不自我更新，其原因尚不清楚。我们发现，在缺乏中线基因活动的胚胎中，像MP2这样的前体通常会分裂成两个神经元，自我更新并同时产生一个神经元。分化后代的身份与不对称定位的决定因素Numb在前体细胞中的分布有关。当这个中线基因过度表达时，它会阻止MP2分裂。Midline蛋白的工作原理是，它通过与启动子的结合来抑制细胞周期蛋白E基因，防止细胞周期蛋白E的过度表达，从而阻止细胞进入细胞周期。在丧失功能的中线突变体中，周期蛋白E的失调允许MP2的一个子细胞像MP2一样重新进入细胞周期，就像周期蛋白E基因的过度表达一样。这些结果表明了一种机制，通过Midline和Cyclin e，限制自我更新的不对称分裂与末端不对称分裂相耦合。这项工作解决了生物学的一个基本问题。
Neuronal precursor cells undergo self-renewing and non-self-renewing asymmetric divisions to generate a large number of neurons of distinct identities. In Drosophila, primary precursor neuroblasts undergo a varying number of self-renewing asymmetric divisions, with one known exception, the MP2 lineage, which undergoes just one terminal asymmetric division similar to the secondary precursor cells. The mechanism and the genes that regulate the transition from self-renewing to non-self-renewing asymmetric division or the number of times a precursor divides is unknown. Here, we show that the T-box transcription factor, Midline (Mid), couples these events. We find that in mid loss of function mutants, MP2 undergoes additional self-renewing asymmetric divisions, the identity of progeny neurons generated dependent upon Numb localization in the parent MP2. MP2 expresses Mid transiently and an over-expression of mid in MP2 can block its division. The mechanism which directs the self-renewing asymmetric division of MP2 in mid involves an upregulation of Cyclin E. Our results indicate that Mid inhibits cyclin E gene expression by binding to a variant Mid-binding site in the cyclin E promoter and represses its expression without entirely abolishing it. Consistent with this, over-expression of cyclin E in MP2 causes its multiple self-renewing asymmetric division. These results reveal a Mid-regulated pathway that restricts the self-renewing asymmetric division potential of cells via inhibiting cyclin E and facilitating their exit from cell cycle. Nerve cells in the brain, spinal cord, gut and so on in all organisms are generated from stem cells. These primary cells divide to self-renew and at the same time generate a secondary precursor cell that terminally divides to produce two cells that differentiate into neurons of different identities, or glial cells or a neuron and a glia. The secondary cells never self-renew, the reason for which is not known. We found that in embryos that lack the activity of a gene called midline, precursors such as MP2 that normally divides into two neurons, self-renews and generates a neuron at the same time. The identity of the differentiating progeny is tied to how the asymmetrically localized determinant Numb is distributed in the precursor cell. When this gene, midline, is over expressed, it blocks MP2 division. The way Midline protein works is that it represses the cyclin E gene via binding to sites in its promoter, preventing the over-expression of Cyclin E and thus blocking cells from entering the cell cycle. A deregulation of cyclin E as in loss of function midline mutants allows one of the daughter cells of MP2 to re-enter cell cycle as MP2, just as an over-expression of the cyclin E gene also does. These results show a mechanism by which restriction on self-renewing asymmetric division is coupled to terminal asymmetric division and works through Midline and Cyclin E. This work addresses one of the fundamental problems is biology.
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影响因子：
4.5
作者：
Manavalan MA;Gaziova I;Bhat KM
通讯作者：
Bhat KM
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
影响因子：
10.5
作者：
Duronio, RJ;Brook, A;OFarrell, PH
通讯作者：
OFarrell, PH
DOI：
10.1073/pnas.96.6.2919
发表时间：
1999-03-16
影响因子：
11.1
作者：
Basson, CT;Huang, TS;Seidman, CE
通讯作者：
Seidman, CE
影响因子：
64.8
作者：
KNOBLICH, JA;JAN, LY;JAN, YN
通讯作者：
JAN, YN