GSE133070
Multiplexed gene editing in the Tmprss11 protease gene cluster reveals a unique role of HAT-like 4 in epidermal barrier formation
The physiological functions of the HAT/DESC sub-family of membrane-anchored serine proteases are poorly defined. The high sequence homology, overlapping pattern of expression, and tight clustering of their corresponding genes have complicated the functional analysis of HAT/DESC proteases by conventional loss-of-function genetics. Here, we exploited the extraordinary efficiency of CRISPR-mediated gene targeting to generate 18 unique congenic mouse strains lacking combinations of HAT/DESC proteases, including a mouse strain deficient in all seven proteases. Surprisingly, mice lacking all HAT/DESC proteases developed to term, were healthy and fertile, and displayed only a modest impairment of epidermal barrier function, as recently described for mice with single deficiency in HAT-like 4. This function of HAT-like 4 in epidermal barrier formation was unique among HAT/DESC proteases. Thus, mice lacking all HAT/DESC proteases displayed transepidermal water loss rates similar to mice lacking only HAT-like 4, and, conversely, mice lacking all HAT/DESC proteases, except HAT-like 4, displayed transepidermal water loss rates identical to wildtype mice. The study yields new insights into the function of HAT/DESC proteases and provides multiple new mouse strains valuable for functional studies of this enigmatic protease sub-family in physiological and in pathophysiological processes. Overall design: Examination of epidermis and tongue in wild-type mice and mice lacking all seven HAT/DESC proteases