Levi G, Topilko P, Schneider-Maunoury S, Lasagna M, Mantero S, Cancedda R, Charnay P
Unité 368 de l'Institut National de la Santé et de la Recherche Médicale, Ecole Normale Supérieure, Paris, France.
Development. 1996 Jan;122(1):113-20. doi: 10.1242/dev.122.1.113.
Endochondral ossification is the prevalent mode of vertebrate skeleton formation; it starts during embryogenesis when cartilage models of long bones develop central regions of hypertrophy which are replaced by bony trabeculae and bone marrow. Although several transcription factors have been implicated in pattern formation in the limbs and axial skeleton, little is known about the transcriptional regulations involved in bone formation. We have created a null allele in the mouse Krox-20 gene, which encodes a zinc finger transcription factor, by in frame insertion of the E. coli lacZ gene and shown that hindbrain segmentation and peripheral nerve myelination are affected in Krox-20-/- embryos. We report here that Krox-20 is also activated in a subpopulation of growth plate hypertrophic chondrocytes and in differentiating osteoblasts and that its disruption severely affects endochondral ossification. Krox-20-/- mice develop skeletal abnormalities including a reduced length and thickness of newly formed bones, a drastic reduction of calcified trabeculae and severe porosity. The periosteal component to bone formation and calcification does not appear to be affected in the homozygous mutant suggesting that the major role for Krox-20 is to be found in the control of the hypertrophic chondrocyte-osteoblast interactions leading to endosteal bone formation.
软骨内成骨是脊椎动物骨骼形成的主要方式；它始于胚胎发育过程中，此时长骨的软骨模型会发育出中央肥大区域，这些区域随后会被骨小梁和骨髓所取代。尽管有几种转录因子与四肢和轴骨骼的模式形成有关，但对于骨形成过程中涉及的转录调控却知之甚少。我们通过在小鼠Krox-20基因（该基因编码一种锌指转录因子）中框内插入大肠杆菌lacZ基因，创建了一个无效等位基因，并表明Krox-20基因敲除的胚胎中后脑节段化和外周神经髓鞘形成受到影响。我们在此报告，Krox-20在生长板肥大软骨细胞亚群以及分化中的成骨细胞中也被激活，并且其缺失严重影响软骨内成骨。Krox-20基因敲除的小鼠会出现骨骼异常，包括新形成骨骼的长度和厚度减少、钙化骨小梁急剧减少以及严重的孔隙率。在纯合突变体中，骨膜对骨形成和钙化的作用似乎未受影响，这表明Krox-20的主要作用在于控制肥大软骨细胞与成骨细胞之间的相互作用，从而导致骨内膜骨形成。
