Hedgehog antagonist RENKCTD11 regulates proliferation and apoptosis of developing granule cell progenitors
Hedgehog antagonist RENKCTD11 regulates proliferation and apoptosis of developing granule cell progenitors
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DOI：
10.1523/jneurosci.2438-05.2005
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发表时间：
2005-09-07
影响因子：
5.3
通讯作者：
Gulino, A
中科院分区：
文献类型：
--
作者：
Argenti, B;Gallo, R;Gulino, A
在小脑的早期发育过程中，颗粒细胞祖细胞（GCP）增殖的爆发发生在外部外部颗粒层（EGL），这主要是由浦肯野细胞衍生的Sonic Hedgehog（Shh）维持的。一旦GCP移动到内部EGL，其中颗粒祖细胞撤回增殖并开始分化并向内部颗粒层（IGL）迁移，Shh反应就中断。不能中断Shh信号导致GCP的不协调增殖和分化，并最终导致恶性肿瘤（即，髓母细胞瘤）。负责GCP生长停滞和分化的Shh抑制机制仍不清楚。在这里，我们报告说，REN，一个假定的肿瘤抑制基因经常删除人髓母细胞瘤，在非增殖内EGL和IGL颗粒细胞比在高度增殖外EGL细胞表达到更高的程度。因此，REN表达上调沿着体外GCP分化，反过来，REN过表达促进生长停滞并增加p27/Kip 1（+）GCP的比例。REN还损害Gli 2依赖的基因转录和Shh增强的靶Gli 1 mRNA的表达，从而拮抗Shh诱导的对培养的GCPs增殖和分化的影响。相反，REN功能性敲低损害Hedgehog拮抗作用和分化，并维持GCP的增殖。最后，REN增强caspase-3激活和末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记凋亡GCP数;因此，REN表达模式、其活性及其对Hedgehog通路的拮抗作用表明，该基因可能代表了从外到内EGL GCP转换时Shh信号的抑制。髓母细胞瘤相关的REN功能丧失可能会撤回这种限制未成熟细胞扩增的信号，从而有利于肿瘤发生。
During the early development of the cerebellum, a burst of granule cell progenitor (GCP) proliferation occurs in the outer external granule layer (EGL), which is sustained mainly by Purkinje cell-derived Sonic Hedgehog (Shh). Shh response is interrupted once GCPs move into the inner EGL, where granule progenitors withdraw proliferation and start differentiating and migrating toward the internal granule layer (IGL). Failure to interrupt Shh signals results in uncoordinated proliferation and differentiation of GCPs and eventually leads to malignancy (i.e., medulloblastoma). The Shh inhibitory mechanisms that are responsible for GCP growth arrest and differentiation remain unclear. Here we report that REN, a putative tumor suppressor frequently deleted in human medulloblastoma, is expressed to a higher extent in nonproliferating inner EGL and IGL granule cells than in highly proliferating outer EGL cells. Accordingly, upregulated REN expression occurs along GCP differentiation in vitro, and, in turn, REN overexpression promotes growth arrest and increases the proportion of p27/Kip1(+) GCPs. REN also impairs both Gli2-dependent gene transcription and Shh-enhanced expression of the target Gli1 mRNA, thus antagonizing the Shh-induced effects on the proliferation and differentiation of cultured GCPs. Conversely, REN functional knock-down impairs Hedgehog antagonism and differentiation and sustains the proliferation of GCPs. Finally, REN enhances caspase-3 activation and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling apoptotic GCP numbers; therefore, the pattern of REN expression, its activity, and its antagonism on the Hedgehog pathway suggest that this gene may represent a restraint of Shh signaling at the outer to inner EGL GCP transitions. Medulloblastoma-associated REN loss of function might withdraw such a limiting signal for immature cell expansion, thus favoring tumorigenesis.