Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo.
Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo.
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DOI：
10.1371/journal.pone.0003517
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Arenas E
中科院分区：
文献类型：
--
作者：
Andersson ER;Prakash N;Cajanek L;Minina E;Bryja V;Bryjova L;Yamaguchi TP;Hall AC;Wurst W;Arenas E
Wnt 5a是一种形态发生素，激活Wnt/平面细胞极性（PCP）通路，并在发育过程中发挥多种功能。PCP信号传导控制上皮平面内细胞的取向以及会聚延伸（CE）运动。Wnt 5a先前被报道在体外促进A9-10多巴胺能（DA）前体的分化。然而，DA细胞中的信号传导机制和Wnt 5a在体内中脑发育中的功能仍不清楚。我们在此报告，Wnt 5a激活DA细胞中的GTdR Rac 1，Rac 1抑制剂阻断腹侧中脑（VM）前体培养物的Wnt 5a诱导的DA神经元分化，将Wnt 5a诱导的分化与Wnt/PCP信号传导的已知效应器联系起来。在体内，Wnt 5a在胚胎（E）9.5天时在整个VM中表达，并且在E11.5-E13.5时局限于VM底板和基板。对Wnt 5a −/−小鼠的分析显示，在E11.5时祖细胞增殖出现短暂增加，在E12.5时出现早熟诱导的NR 4A 2+（Nurr 1）前体池。过量的NR 4A 2+前体保持未分化，直到E14.5，当检测到DA神经元瞬时增加25%。Wnt 5a −/−小鼠也表现出（中）脑形态发生的缺陷，包括中脑伸长和圆形脑室腔的损伤。有趣的是，这些改变主要影响DA谱系中的细胞。腹侧Sonic hedgehog表达域变宽变平，是典型的CE表型，Ngn 2 + DA祖细胞、NR 4A 2 + DA前体细胞和TH+ DA神经元所占据的域在吻尾侧减少并侧向扩展。总之，我们在此描述了Wnt 5a在DA谱系中对Wnt/PCP信号传导的调节，并为Wnt 5a在体内VM中的多种功能提供了证据，包括VM形态发生、DA祖细胞分裂和NR 4A 2 + DA前体的分化的调节。
Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9–10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5–E13.5. Analysis of Wnt5a−/− mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a−/− mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors.
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影响因子：
10.5
作者：
Habas, R;Dawid, IB;He, X
通讯作者：
He, X
DOI：
10.1073/pnas.0611356104
发表时间：
2007-04-17
影响因子：
11.1
作者：
Bryja, Vitezslav;Gradl, Dietmar;Schulte, Gunnar
通讯作者：
Schulte, Gunnar
影响因子：
10.5
作者：
Goodrich, LV;Johnson, RL;Scott, MP
通讯作者：
Scott, MP
影响因子：
2.6
作者：
Kilian, B;Mansukoski, H;Heisenberg, CP
通讯作者：
Heisenberg, CP
DOI：
10.1073/pnas.1534900100
发表时间：
2003-10-28
影响因子：
11.1
作者：
Castelo-Branco, GA;Wagner, J;Arenas, E
通讯作者：
Arenas, E