Proteolytic release of membrane bound intercellular regulators

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Abstract
The investigators created mutations targeted to TACE (tace −Zn/−Zn mice). The zinc binding domains of this enzyme were thereby deleted, causing inactivation of the metalloproteinase activity. TNF-α release was therefore efficiently blocked. Crossbreeding of mice heterozygous for this mutation (tace −Zn/+Znmice) surprisingly resulted in a notable under-representation oftace −Zn/−Zn mice, probably as a result of intrauterine death. The studies showed that mosttace −Zn/−Zn mice died between day 17.5 and the first day after birth. As mice lacking TNF or its receptor are overtly normal, it was suspected that TACE has activities in addition to release of TNF. Surprisingly, surviving newborn tace −Zn/−Zn mice had phenotypic features similar to those of mice lacking TGF-α1 , 2 such as open eye lids (eye lids do normally not open until postnatal day 14), perturbed hair coats and curly vibrissae.