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Multiplexed gene editing in the Tmprss11 protease gene cluster reveals a unique role of HAT-like 4 in epidermal barrier formation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE133070 | GEO | 2020/04/14

REPOSITORIES: GEO

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Project description:Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, & Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 & Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization and sebaceous gland function. This data indicates that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.

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Multiplexed gene editing in the Tmprss11 protease gene cluster reveals a unique role of HAT-like 4 in epidermal barrier formation

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