Vaillant Catherine, Michos Odyssé, Orolicki Slobodanka, Brellier Florence, Taieb Sabrina, Moreno Eliza, Té Hélène, Zeller Rolf, Monard Denis
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, Switzerland.
Development. 2007 May;134(9):1745-54. doi: 10.1242/dev.02840. Epub 2007 Apr 4.
Development of the postnatal cerebellum relies on the tight regulation of cell number by morphogens that control the balance between cell proliferation, survival and differentiation. Here, we analyze the role of the serine-protease inhibitor protease nexin 1 (PN-1; SERPINE2) in the proliferation and differentiation of cerebellar granular neuron precursors (CGNPs) via the modulation of their main mitogenic factor, sonic hedgehog (SHH). Our studies show that PN-1 interacts with low-density lipoprotein receptor-related proteins (LRPs) to antagonize SHH-induced CGNP proliferation and that it inhibits the activity of the SHH transcriptional target GLI1. The binding of PN-1 to LRPs interferes with SHH-induced cyclin D1 expression. CGNPs isolated from Pn-1-deficient mice exhibit enhanced basal proliferation rates due to overactivation of the SHH pathway and show higher sensitivity to exogenous SHH. In vivo, the Pn-1 deficiency alters the expression of SHH target genes. In addition, the onset of CGNP differentiation is delayed, which results in an enlarged outer external granular layer. Furthermore, the Pn-1 deficiency leads to an overproduction of CGNPs and to enlargement of the internal granular layer in a subset of cerebellar lobes during late development and adulthood. We propose that PN-1 contributes to shaping the cerebellum by promoting cell cycle exit.
出生后小脑的发育依赖于形态发生素对细胞数量的严格调控，这些形态发生素控制着细胞增殖、存活和分化之间的平衡。在此，我们通过调节小脑颗粒神经元前体细胞（CGNP）的主要促有丝分裂因子音猬因子（SHH），分析丝氨酸蛋白酶抑制剂蛋白酶nexin 1（PN-1；SERPINE2）在CGNP增殖和分化中的作用。我们的研究表明，PN-1与低密度脂蛋白受体相关蛋白（LRP）相互作用，拮抗SHH诱导的CGNP增殖，并且它抑制SHH转录靶点GLI1的活性。PN-1与LRP的结合干扰了SHH诱导的细胞周期蛋白D1表达。从Pn-1基因缺失小鼠中分离出的CGNP由于SHH信号通路过度激活而表现出基础增殖率增强，并且对外源性SHH表现出更高的敏感性。在体内，Pn-1基因缺失改变了SHH靶基因的表达。此外，CGNP分化的起始延迟，导致外颗粒层增大。此外，Pn-1基因缺失导致CGNP过度产生，并在发育后期和成年期的一部分小脑叶中导致内颗粒层增大。我们提出，PN-1通过促进细胞周期退出，有助于塑造小脑。
