S. Narisawa et al., INACTIVATION OF 2 MOUSE ALKALINE-PHOSPHATASE GENES AND ESTABLISHMENT OF A MODEL OF INFANTILE HYPOPHOSPHATASIA, Developmental dynamics, 208(3), 1997, pp. 432-446
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.