Antagonism between Gdf6a and retinoic acid pathways controls timing of retinal neurogenesis and growth of the eye in zebrafish.
Antagonism between Gdf6a and retinoic acid pathways controls timing of retinal neurogenesis and growth of the eye in zebrafish.
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DOI：
10.1242/dev.130922
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发表时间：
2016-04-01
期刊：
影响因子：
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通讯作者：
Cerveny KL
中科院分区：
文献类型：
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作者：
Valdivia LE;Lamb DB;Horner W;Wierzbicki C;Tafessu A;Williams AM;Gestri G;Krasnow AM;Vleeshouwer-Neumann TS;Givens M;Young RM;Lawrence LM;Stickney HL;Hawkins TA;Schwarz QP;Cavodeassi F;Wilson SW;Cerveny KL
在生长的组织中维持神经发生需要祖细胞增殖和分化之间的紧密平衡。在斑马鱼视网膜中，神经元分化分两个阶段进行，中央视网膜的胚胎视网膜祖细胞（RPC）负责第一轮分化，而来自睫状边缘区（CMZ）的干细胞负责晚期神经发生和眼睛的生长。在这项研究中，我们分析了两个小眼睛的突变体，在视网膜神经发生的早期和晚期阶段显示缺陷。这些突变体携带gdf6a的病变，gdf6a是编码BMP家族成员的基因，以前与眼睛的背腹图案有关。我们发现，gdf6a突变的眼睛表现出扩大视黄酸（RA）信号转导，并证明在野生型眼睛外源性激活这一途径抑制视网膜生长，产生小眼睛减少CMZ和增殖的祖细胞，类似于gdf6a突变体。我们提供的证据表明，RA调节RPC分化的时间，促进细胞周期退出。此外，减少gdf6a突变体中的RA信号传导重建胚胎视网膜神经发生的适当时机，并恢复CMZ中假定的干细胞和祖细胞群体。总之，我们的研究结果支持了一个模型，其中背侧表达的gdf6a限制RA通路活性，以控制从增殖到分化的过渡，在不断增长的眼睛。总结：在脊椎动物的眼睛中，背侧表达的Gdf6a限制RA通路活性以控制从增殖到分化的转变，从而调节眼睛大小。
Maintaining neurogenesis in growing tissues requires a tight balance between progenitor cell proliferation and differentiation. In the zebrafish retina, neuronal differentiation proceeds in two stages with embryonic retinal progenitor cells (RPCs) of the central retina accounting for the first rounds of differentiation, and stem cells from the ciliary marginal zone (CMZ) being responsible for late neurogenesis and growth of the eye. In this study, we analyse two mutants with small eyes that display defects during both early and late phases of retinal neurogenesis. These mutants carry lesions in gdf6a, a gene encoding a BMP family member previously implicated in dorsoventral patterning of the eye. We show that gdf6a mutant eyes exhibit expanded retinoic acid (RA) signalling and demonstrate that exogenous activation of this pathway in wild-type eyes inhibits retinal growth, generating small eyes with a reduced CMZ and fewer proliferating progenitors, similar to gdf6a mutants. We provide evidence that RA regulates the timing of RPC differentiation by promoting cell cycle exit. Furthermore, reducing RA signalling in gdf6a mutants re-establishes appropriate timing of embryonic retinal neurogenesis and restores putative stem and progenitor cell populations in the CMZ. Together, our results support a model in which dorsally expressed gdf6a limits RA pathway activity to control the transition from proliferation to differentiation in the growing eye. Summary: In the vertebrate eye, dorsally expressed Gdf6a limits RA pathway activity to control the transition from proliferation to differentiation, thereby regulating eye size.