Narisawa S, Fröhlander N, Millán J L
The Burnham Institute, La Jolla Cancer Research Center, California 92037, USA.
Dev Dyn. 1997 Mar;208(3):432-46. doi: 10.1002/(SICI)1097-0177(199703)208:3<432::AID-AJA13>3.0.CO;2-1.
We report the inactivation, via homologous recombination, of two of the three active mouse alkaline phosphatase genes, i.e., embryonic (EAP) and tissue nonspecific (TNAP). Whereas expression of the EAP isozyme was abolished in all tissues that express EAP developmentally (such as the preimplantation embryo, thymus, and testis), the EAP knock-out mice show no obvious phenotypic abnormalities. They reproduce normally and give birth to live offspring, indicating the nonessential role of EAP during embryonic development. Mice deficient in the TNAP gene mimic a severe form of hypophosphatasia. These TNAP-/- mice are growth impaired, develop epileptic seizures and apnea, and die before weaning. Examination of the tissues indicates abnormal bone mineralization and morphological changes in the osteoblasts, aberrant development of the lumbar nerve roots, disturbances in intestinal physiology, increased apoptosis in the thymus, and abnormal spleens. Our results indicate that, in the mouse, TNAP appears not to be essential for the initial events leading to bone mineral deposition but that TNAP seems to play a role in the maintenance of this process after birth. The other phenotypic manifestations may be a consequence of the lack of TNAP in the developing neural tube between stages E8.5 and E13.5 of embryogenesis. We hypothesize that the autonomic nervous system is compromised in these TNAP-/- mice.
我们报道了通过同源重组使三个有活性的小鼠碱性磷酸酶基因中的两个失活，即胚胎型（EAP）和组织非特异性型（TNAP）。虽然EAP同工酶在所有发育过程中表达EAP的组织（如植入前胚胎、胸腺和睾丸）中均不再表达，但EAP基因敲除小鼠未表现出明显的表型异常。它们正常繁殖并产下活的后代，表明EAP在胚胎发育过程中并非必需。TNAP基因缺陷的小鼠表现出严重型低磷酸酯酶症。这些TNAP-/-小鼠生长受限，出现癫痫发作和呼吸暂停，并在断奶前死亡。对组织的检查显示骨矿化异常和成骨细胞形态改变、腰神经根发育异常、肠道生理紊乱、胸腺细胞凋亡增加以及脾脏异常。我们的结果表明，在小鼠中，TNAP似乎对于导致骨矿沉积的初始事件并非必需，但TNAP似乎在出生后该过程的维持中发挥作用。其他表型表现可能是胚胎发育阶段E8.5至E13.5期间发育中的神经管中缺乏TNAP的结果。我们推测这些TNAP-/-小鼠的自主神经系统受损。
