Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development
Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development
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DOI：
10.1242/dev.01438
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发表时间：
2004-11-01
期刊：
影响因子：
4.6
通讯作者：
Joyner, AL
中科院分区：
文献类型：
--
作者：
Corrales, JMD;Rocco, GL;Joyner, AL
小脑由一组高度组织化的叶叶组成，这些叶叶主要是在出生后在颗粒细胞前体（GCP）池的扩张过程中产生的。由于分泌因子sonic hedgehog （Shh）在浦肯野细胞中表达，并在体外作为GCP丝裂原发挥作用，因此Shh可能通过调节小脑叶的位置和/或大小来影响小脑发育过程中的叶面形成。我们研究了Shh及其转录介质Gli蛋白如何在体内调节GCP增殖，并测试了它们是否影响叶面形成。我们证明Shh的表达在空间和时间上与叶理形成相关。Shh靶基因Gli1的表达在小脑前部内侧也最高，但仅限于增殖的GCPs和Bergmann胶质细胞。相比之下，Gli2在发育中的小脑除浦肯野细胞外的所有细胞中均匀表达，Gli3沿前后轴广泛表达。glii突变体具有正常的小脑，而Gli2突变体在出生时叶面发育大大减少，gcp减少。在一项使用转基因小鼠的补充研究中，我们发现在正常区域过表达Shh不会严重改变基本叶状结构，但确实会导致gcp的增殖延长和小脑的总体大小增加。综上所述，这些研究表明，通过Gli2产生的阳性Shh信号是产生足够数量的gcp以实现正常叶生长所必需的。
The cerebellum consists of a highly organized set of folia that are largely generated postnatally during expansion of the granule cell precursor (GCP) pool. Since the secreted factor sonic hedgehog (Shh) is expressed in Purkinje cells and functions as a GCP mitogen in vitro, it is possible that Shh influences foliation during cerebellum development by regulating the position and/or size of lobes. We studied how Shh and its transcriptional mediators, the Gli proteins, regulate GCP proliferation in vivo, and tested whether they influence foliation. We demonstrate that Shh expression correlates spatially and temporally with foliation. Expression of the Shh target gene Gli1 is also highest in the anterior medial cerebellum, but is restricted to proliferating GCPs and Bergmann glia. By contrast, Gli2 is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and Gli3 is broadly expressed along the anteroposterior axis. Whereas Gli mutants have a normal cerebellum, Gli2 mutants have greatly reduced foliation at birth and a decrease in GCPs. In a complementary study using transgenic mice, we show that overexpressing Shh in the normal domain does not grossly alter the basic foliation pattern, but does lead to prolonged proliferation of GCPs and an increase in the overall size of the cerebellum. Taken together, these studies demonstrate that positive Shh signaling through Gli2 is required to generate a sufficient number of GCPs for proper lobe growth.