Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors.
Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors.
复制标题
DOI：
10.1371/journal.pgen.1009371
复制
发表时间：
2021-03
期刊：
影响因子：
4.5
通讯作者：
Zhu S
中科院分区：
文献类型：
--
作者：
Chen R;Hou Y;Connell M;Zhu S
为了增加神经干细胞产生的神经元的数量和多样性，中间神经祖细胞（intermediate neural progenitor, INPs）需要通过避免去分化和过早分化来维持其体内平衡。阐明INP如何维持体内平衡对于理解脑复杂性的产生和INP发育缺陷导致的各种神经系统疾病至关重要。在这里，我们报道了在果蝇II型神经母细胞（NB）谱系中表达的Six4可以阻止多余的II型NBs的产生和INPs的过早分化。我们发现，Six4的缺失可能导致额外的II型NBs，这可能是由于未成熟INPs （imINPs）的去分化。我们提供的数据进一步证明，Six4通过与Earmuff和PntP1形成三聚体复合物，在一定程度上抑制了imINPs中PntP1的表达和活性。此外，Six4的敲低通过增强imINPs中的异位Prospero表达，加剧了PntP1缺失导致的INPs缺失，这表明Six4也是防止INPs过早分化所必需的。综上所述，我们的工作确定了一种新的转录因子，可能在维持INP稳态中起重要作用。中间神经祖细胞（Intermediate neural progenitor, INPs）是神经干细胞的后代，可以在短期内增殖以增加大脑中产生的神经细胞的数量。INPs在决定大脑的大小和复杂程度方面起着关键作用。为了发挥它们的功能，INPs需要维持自己的种群，不能采用神经干细胞的身份，这一过程被称为去分化，也不能获得自己的子细胞的命运，过早地停止增殖，这一过程被称为过早分化。然而，INPs如何避免去分化和过早分化尚不完全清楚。在这项研究中，我们发现一种名为Six4的蛋白质是一种新的因子，在发育中的果蝇大脑中，它在阻止额外神经干细胞的产生和INPs的过早分化中起着重要作用。我们描述了Six4如何在功能和物理上与其他参与调节INP细胞命运规范的因素相互作用。我们的工作为INP发育的调节机制提供了新的见解，并可能对理解正常发育过程中复杂的大脑是如何产生的，以及当INP不能避免过早分化或去分化时，大脑发育异常或脑肿瘤是如何发生的具有重要意义。
In order to boost the number and diversity of neurons generated from neural stem cells, intermediate neural progenitors (INPs) need to maintain their homeostasis by avoiding both dedifferentiation and premature differentiation. Elucidating how INPs maintain homeostasis is critical for understanding the generation of brain complexity and various neurological diseases resulting from defects in INP development. Here we report that Six4 expressed in Drosophila type II neuroblast (NB) lineages prevents the generation of supernumerary type II NBs and premature differentiation of INPs. We show that loss of Six4 leads to supernumerary type II NBs likely due to dedifferentiation of immature INPs (imINPs). We provide data to further demonstrate that Six4 inhibits the expression and activity of PntP1 in imINPs in part by forming a trimeric complex with Earmuff and PntP1. Furthermore, knockdown of Six4 exacerbates the loss of INPs resulting from the loss of PntP1 by enhancing ectopic Prospero expression in imINPs, suggesting that Six4 is also required for preventing premature differentiation of INPs. Taken together, our work identified a novel transcription factor that likely plays important roles in maintaining INP homeostasis. Intermediate neural progenitors (INPs) are descendants of neural stem cells that can proliferate for a short term to amplify the number of nerve cells generated in the brain. INPs play critical roles in determining how big and complex a brain can grow. To perform their function, INPs need to maintain their own population and must not adopt the identity of neural stem cells, a process called dedifferentiation, or acquire the fate of their own daughter cells and stop proliferation too soon, a process called premature differentiation. However, how INPs avoid dedifferentiation and premature differentiation is not fully understood. In this study, we identified a protein called Six4 as a novel factor that plays important roles in preventing the generation of extra neural stem cells and premature differentiation of INPs in developing fruit fly brains. We described how Six4 functionally and physically interacts with other factors that are involved in regulating INP cell fate specification. Our work provides novel insights into the mechanisms regulating INP development and could have important implications in understanding how complex brains are generated during normal development and how abnormal brain development or brain tumor can occur when INPs fail to avoid premature differentiation or dedifferentiation.
登录
查看更多内容
影响因子：
11.8
作者：
Janssens DH;Hamm DC;Anhezini L;Xiao Q;Siller KH;Siegrist SE;Harrison MM;Lee CY
通讯作者：
Lee CY
影响因子：
4.6
作者：
Janssens, Derek H.;Komori, Hideyuki;Lee, Cheng-Yu
通讯作者：
Lee, Cheng-Yu
Notch和EGFR信号传导来自神经源性位置的不同神经细胞身份的序列规范。
DOI：
10.1242/dev.055681
发表时间：
2011-07
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Hwang HJ;Rulifson E
通讯作者：
Rulifson E
影响因子：
10.5
作者：
BIER, E;VAESSIN, H;JAN, YN
通讯作者：
JAN, YN
影响因子：
64.5
作者：
Eroglu, Elif;Burkard, Thomas R.;Knoblich, Juergen A.
通讯作者：
Knoblich, Juergen A.