Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher.
Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher.
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DOI：
10.1371/journal.pgen.1000136
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发表时间：
2008-07-25
期刊：
影响因子：
4.5
通讯作者：
Roehl HH
中科院分区：
文献类型：
--
作者：
Clément A;Wiweger M;von der Hardt S;Rusch MA;Selleck SB;Chien CB;Roehl HH
人类外骨蛋白基因 (EXT) 的突变会导致一种称为遗传性多发性外骨疣 (HME) 的疾病，影响普通人群中五万分之一的人。 HME 患者身材矮小，并在儿童时期出现骨软骨瘤。在这里，我们展示了两种斑马鱼突变体，dackel（dak）和pinscher（pic），具有与 HME 患者中所见的软骨缺陷非常相似的软骨缺陷。我们之前已经确定 dak 编码斑马鱼 Ext2。 pic 的定位克隆表明它编码聚糖硫酸化所需的硫酸盐转运蛋白 (Papst1)。我们发现，虽然 dak 和 pic 在软骨形态发生过程中都是必需的，但它们对于软骨细胞和软骨膜细胞分化来说是可有可无的。它们也是肥大软骨细胞分化和成骨细胞分化所必需的。移植分析表明，dak−/− 细胞通常被邻近的野生型软骨细胞拯救。相比之下，pic−/− 软骨细胞总是自主行动，并且可以破坏邻近野生型细胞的形态。这些发现导致了一种新模型的开发来解释 HME 的病因学。遗传性多发性外生骨疣是一种导致儿童良性骨肿瘤形成的疾病。除了引起严重的骨骼畸形外，骨肿瘤还会压迫神经或其他组织，导致慢性疼痛。虽然肿瘤通常可以通过手术切除，但有时会复发或处于无法进行手术的位置。我们已经鉴定出两种斑马鱼品系，它们的后代具有与遗传性多发性外生骨疣患者相似的骨骼缺陷。我们发现每种菌株都携带一种必需基因的突变形式。重要的是，这两个基因也在人类中发现，因此通过分析它们在斑马鱼中的功能，我们可以阐明它们在人类中的作用。我们的研究阐明了这些基因在正常骨骼发育过程中的作用，并使我们能够建立一个模型来解释基因变化如何导致人类骨肿瘤。
Mutations in human Exostosin genes (EXTs) confer a disease called Hereditary Multiple Exostoses (HME) that affects 1 in 50,000 among the general population. Patients with HME have a short stature and develop osteochondromas during childhood. Here we show that two zebrafish mutants, dackel (dak) and pinscher (pic), have cartilage defects that strongly resemble those seen in HME patients. We have previously determined that dak encodes zebrafish Ext2. Positional cloning of pic reveals that it encodes a sulphate transporter required for sulphation of glycans (Papst1). We show that although both dak and pic are required during cartilage morphogenesis, they are dispensable for chondrocyte and perichondral cell differentiation. They are also required for hypertrophic chondrocyte differentiation and osteoblast differentiation. Transplantation analysis indicates that dak−/− cells are usually rescued by neighbouring wild-type chondrocytes. In contrast, pic−/− chondrocytes always act autonomously and can disrupt the morphology of neighbouring wild-type cells. These findings lead to the development of a new model to explain the aetiology of HME. Hereditary Multiple Exostoses is a disease that causes the formation of benign bone tumours in children. Besides causing severe skeletal deformity, the bone tumours can compress nerves or other tissue resulting in chronic pain. Although the tumours can usually be surgically removed, they sometimes recur or are in positions that prevent surgery. We have identified two strains of zebrafish whose offspring have skeletal defects that resemble those of patients with Hereditary Multiple Exostoses. We have found that each strain carries a mutated form of an essential gene. Importantly, these two genes are also found in humans, and thus by analysing their function in zebrafish, we may shed light on their role in humans. Our study has elucidated the roles of these genes during normal skeletal development and has allowed us to generate a model for how genetic changes give rise to bone tumours in humans.
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DOI：
10.1016/j.biocel.2005.03.006
发表时间：
2005-09-01
影响因子：
4
作者：
Cool, SM;Nurcombe, V
通讯作者：
Nurcombe, V
影响因子：
4.1
作者：
Hecht, JT;Hall, CR;Cole, WG
通讯作者：
Cole, WG
影响因子：
4.3
作者：
Ito, Y;Hikino, M;Sugahara, K
通讯作者：
Sugahara, K
影响因子：
2.9
作者：
KELLER, KM;BRAUER, PR;KELLER, JM
通讯作者：
KELLER, JM
影响因子：
2.6
作者：
Bruneau, S;Mourrain, P;Rosa, FM
通讯作者：
Rosa, FM