Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects
Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects
复制标题
DOI：
10.1093/hmg/ddl053
复制
发表时间：
2006-04-15
影响因子：
3.5
通讯作者：
Culiat, CT
中科院分区：
文献类型：
--
作者：
Desai, J;Shannon, ME;Culiat, CT
哺乳动物Nell 1基因编码蛋白激酶C-β 1（PKC-β 1）结合蛋白，属于一类控制细胞生长和分化的新型细胞信号分子。在人类和小鼠中，Nell 1在发育中的颅缝中的过度表达诱导颅缝早闭，即生长中的颅骨前缘的过早融合。在这里，我们报告的代，定位克隆和表征的Nell 1（6 R），一个隐性的，在小鼠Nell 1基因的胚胎致死点突变，诱导N-乙基-N-亚硝基脲。Nell 1（6 R）具有T -> A碱基变化，其将半胱氨酸密码子转化为提前终止密码子[Cys（502）Ter]，导致预测的蛋白质产物的严重截短和转录物稳态水平的显著降低。除了预期的颅骨形态改变外，Nell 1（6 R）突变体还表现出脊柱和胸腔的骨骼缺陷，揭示了Nell 1在软骨内成骨信号传导中迄今为止尚未确定的作用。对219个基因的实时定量逆转录PCR分析显示，Nell 1功能丧失与细胞外基质（ECM）蛋白基因表达减少之间存在关联，ECM蛋白对软骨形成和骨形成至关重要。几个受影响的基因涉及人类软骨疾病埃勒斯-丹洛斯综合征和其他与脊柱弯曲异常相关的疾病。Nell 1（6 R）突变小鼠是一种新的工具，用于阐明发育中的颅骨和脊柱中成骨细胞和软骨细胞分化的基本机制，并了解ECM蛋白质生产中的扰动如何导致这些结构的异常。
The mammalian Nell1 gene encodes a protein kinase C-beta 1 (PKC-beta 1) binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Over-expression of Nell1 in the developing cranial sutures in both human and mouse induces craniosynostosis, the premature fusion of the growing cranial bone fronts. Here, we report the generation, positional cloning and characterization of Nell1(6R), a recessive, neonatal-lethal point mutation in the mouse Nell1 gene, induced by N-ethyl-N-nitrosourea. Nell1(6R) has a T -> A base change that converts a codon for cysteine into a premature stop codon [Cys(502)Ter], resulting in severe truncation of the predicted protein product and marked reduction in steady-state levels of the transcript. In addition to the expected alteration of cranial morphology, Nell1(6R) mutants manifest skeletal defects in the vertebral column and ribcage, revealing a hitherto undefined role for Nell1 in signal transduction in endochondral ossification. Real-time quantitative reverse transcription-PCR assays of 219 genes showed an association between the loss of Nell1 function and reduced expression of genes for extracellular matrix (ECM) proteins critical for chondrogenesis and osteogenesis. Several affected genes are involved in the human cartilage disorder Ehlers-Danlos Syndrome and other disorders associated with spinal curvature anomalies. Nell1(6R) mutant mice are a new tool for elucidating basic mechanisms in osteoblast and chrondrocyte differentiation in the developing skull and vertebral column and understanding how perturbations in the production of ECM proteins can lead to anomalies in these structures.