INACTIVATION OF 2 MOUSE ALKALINE-PHOSPHATASE GENES AND ESTABLISHMENT OF A MODEL OF INFANTILE HYPOPHOSPHATASIA

We report the inactivation, via homologous recombination, of two of th e 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 mi ce show no obvious phenotypic abnormalities, They reproduce normally a nd give birth to live offspring, indicating the nonessential role of E AP during embryonic development, Mice deficient in the TNAP gene mimic a severe form of hypophosphatasia. These TNAP-/- mice are growth impa ired, develop epileptic seizures and apnea, and die before weaning, Ex amination of the tissues indicates abnormal bone mineralization and mo rphological changes in the osteoblasts, aberrant development of the lu mbar nerve roots, disturbances in intestinal physiology, increased apo ptosis 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 develop ing neural tube between stages E8.5 and E13.5 of embryogenesis. We hyp othesize that the autonomic nervous system is compromised in these TNA P-/- mice. (C) 1997 Wiley-Liss, Inc.