Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors.
Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors.
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DOI：
10.1007/s12015-023-10600-7
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发表时间：
2023-11
影响因子：
4.8
通讯作者：
Lupo, Giuseppe
中科院分区：
文献类型：
--
作者：
Giuliani, Andrea;Licursi, Valerio;Nisi, Paola S.;Fiore, Mario;D'Angelo, Sara;Biagioni, Stefano;Negri, Rodolfo;Rugg-Gunn, Peter J.;Cacci, Emanuele;Lupo, Giuseppe
关键词：
在成年小鼠大脑中，侧脑室下方的脑室下区（SVZ）蕴藏着一群静止的神经干细胞，它们可以被激活（aNSCs）来启动增殖，并产生一个由转运扩增祖细胞（TAPs）、神经母细胞（NBs）和新生神经元组成的神经源性谱系。这一过程在老化过程中显著减少。最近的研究表明，衰老的SVZ生态位通过引起促进NSC静止的转录组变化，减少了增殖的神经/干细胞祖细胞（NSPCs）池，从而减少了成体神经发生。然而，介导这些变化的转录因子仍不清楚。我们之前发现，在老龄小鼠SVZ的NSPC中，同源盒基因Dbx2上调，可以抑制NSPC培养物的生长。在这里，我们进一步研究了它作为神经源性衰退的候选转录调节剂的作用。我们发现，Dbx2的表达受表皮生长因子受体信号的下调，促进NSPC的增殖，并在衰老的SVZ中减少。通过过表达Dbx2的转基因NSPC株系，我们还发现该基因通过阻碍G2/M转变来抑制NSPC的增殖。此外，我们利用转基因NSPCs的RNA测序来阐明Dbx2调控的转录组网络。在最热门的研究中，我们报道了与细胞周期进程有关的分子途径的下调。因此，我们发现Dbx2功能与增殖性NSPCs （ansc、TAPs和早期NBs）的转录特征呈负相关。这些结果表明Dbx2是一个转录因子，将衰老生态位的抗神经原性输入传递给NSPC转录组。在线版本包含补充资料，网址为10.1007/s12015-023-10600-7。
In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging. Recent studies suggest that the aged SVZ niche decreases the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that promote NSC quiescence. The transcription factors that mediate these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of NSPC cultures. Here, we further investigate its role as a candidate transcriptional regulator of neurogenic decline. We show that Dbx2 expression is downregulated by Epidermal Growth Factor receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines overexpressing Dbx2, we also show that this gene inhibits NSPC proliferation by hindering the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptomic networks modulated by Dbx2. Among the top hits, we report the downregulation of the molecular pathways implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a transcription factor relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome. The online version contains supplementary material available at 10.1007/s12015-023-10600-7.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
4.3
作者：
Cochard LM;Levros LC Jr;Joppé SE;Pratesi F;Aumont A;Fernandes KJL
通讯作者：
Fernandes KJL
影响因子：
3.7
作者：
Soldati C;Cacci E;Biagioni S;Carucci N;Lupo G;Perrone-Capano C;Saggio I;Augusti-Tocco G
通讯作者：
Augusti-Tocco G
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J