Phenotypes Associated with This Genotype

Genotype
MGI:8211395

• Allelic Composition: Spink5^tm2.1Hov/Spink5^tm2.1Hov; Tg(KRT5-cre/ERT2)2Ipc/0
• Genetic Background: involves: C57BL/6 * C57BL/6JRj * SJL

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:357366 )

• survival of tamoxifen-treated mice depends on severity and extent of skin lesions with a mean survival time of 8 weeks

integument

increased keratinocyte proliferation ( J:357366 )

• tamoxifen-treated mice exhibit increased cell proliferation in all basal layer cells and in some suprabasal layer cells of the epidermis

impaired skin barrier function ( J:357366 )

• epidermal barrier of tamoxifen-treated mice is severely compromised, with average transepidermal water loss values on dorsal skin 8 times higher than in controls

• transepidermal water loss values remain high over time and magnitude is correlated with severity of skin lesions

skin inflammation ( J:357366 )

• skin of tamoxifen-treated mice exhibits a 3-fold increase of mast cells, a 9-fold increase of neutrophils, 1.6-fold increase in macrophages, 8.2-fold increase in B cells, 2.5-fold increase in T cells, 3.9-fold increase in IL-17A+ cells and 7.4-fold increase in FOXP3+ cells

• tamoxifen-treated mice show a multiform skin inflammation featured by infiltration of neutrophils, IL-17A+ cells, and B cells, keratinocyte-specific expression of IL-36A and IL-24 cytokines and activated JAK/STAT3 signaling in epidermis and dermis

alopecia ( J:357366 )

• mice develop alopecic areas following tamoxifen treatment

focal hair loss ( J:357366 )

• tamoxifen-treated mice exhibit hair loss at sites of skin lesions

loss of vibrissae ( J:357366 )

• tamoxifen-treated mice exhibit loss of vibrissae hairs at sites of skin lesions

abnormal skin morphology ( J:357366 )

• skin of tamoxifen-treated mice shows presence of subcorneal neutrophilic microabscesses

abnormal keratinocyte differentiation ( J:357366 )

• marker analysis suggests abnormal keratinocyte differentiation in tamoxifen-treated mice

abnormal dermal layer morphology ( J:357366 )

• reduction of CD34+ fibroblasts in the dermis of tamoxifen-treated mice

abnormal epidermis stratum corneum morphology ( J:357366 )

• tamoxifen-treated mice show stratum corneum detachment

hyperkeratosis ( J:357366 )

• in tamoxifen-treated mice

parakeratosis ( J:357366 )

• in tamoxifen-treated mice

thick epidermis ( J:357366 )

• epidermal thickening is increased by 4-fold in tamoxifen-treated mice

scaly skin ( J:357366 )

• mice develop red, scaly and crusty skin with alopecic areas secondary to scratching behavior following tamoxifen treatment

skin lesions ( J:357366 )

• mice develop skin lesions resembling Netherton syndrome within 10 days after starting tamoxifen treatment

• about 40% of mice exhibit spontaneous, tamoxifen-independent floxed allele excision as early as 2 weeks after birth due to the leaky nature of the transgene and develop skin lesions

• treatment of tamoxifen-treated mice with a broad-spectrum antibiotics cocktail does not reduce skin lesion severity

• however, tamoxifen-treated mice do not show differences in skin bacterial load from controls

abnormal skin development ( J:357366 )

• tamoxifen-treated mice exhibit abnormal epidermal differentiation

growth/size/body

weight loss ( J:357366 )

• skin lesions in tamoxifen-treated mice are accompanied by weight loss and signs of emaciation in the most severe cases

cachexia ( J:357366 )

• the most severe cases of skin lesions in tamoxifen-treated mice are accompanied by signs of emaciation

enlarged spleen ( J:357366 )

• tamoxifen-treated mice exhibit an enlarged spleen as adult mice (> 6 weeks of age)

homeostasis/metabolism

increased enzyme/coenzyme level ( J:357366 )

• activity of trypsin-like serine proteases in skin extracts from tamoxifen-treated mice is increased 19-fold

• trypsin-like and chymotrypsin-like serine protease activities are increased in thymus tissues of tamoxifen-treated mice

impaired skin barrier function ( J:357366 )

• epidermal barrier of tamoxifen-treated mice is severely compromised, with average transepidermal water loss values on dorsal skin 8 times higher than in controls

• transepidermal water loss values remain high over time and magnitude is correlated with severity of skin lesions

decreased collagen level ( J:357366 )

• reduction of collagen fibers in the dermis of tamoxifen-treated mice

increased chemokine level ( J:357366 )

• the pro-inflammatory cytokine IL-36A is increased 4-fold in the epidermis, IL-24 is increased 15-fold in all epidermal layers , and CXCL3, a chemotactic factor for neutrophils is strongly expressed in immune cells infiltrating the dermis and less weakly in epidermis

hematopoietic system

abnormal thymus morphology ( J:357366 )

• trypsin-like and chymotrypsin-like serine protease activities are increased in thymus tissues of tamoxifen-treated mice

• treatment with broad-spectrum antibiotics does not affect serine protease activity in thymus

thymus cortex hypoplasia ( J:357366 )

• thymus cortex area are reduced due to depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

small thymus ( J:357366 )

• thymus size is drastically reduced in tamoxifen-treated mice

thymus atrophy ( J:357366 )

• tamoxifen-treated mice exhibit thymic atrophy characterized by depletion of CD4+CD8+ thymocytes, and increased serine protease activity

• treatment of tamoxifen-treated mice with a broad-spectrum antibiotics cocktail does not reduce thymic atrophy

thymus hypoplasia ( J:357366 )

• thymus cellularity is reduced due to depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

decreased double-positive T cell number ( J:357366 )

• depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

arrested T cell differentiation ( J:357366 )

• thymus shows arrest of thymocyte development at the double positive stage in tamoxifen-treated mice, however the few remaining double positive thymocytes can undergo positive selection as CD4+ or CD8+ single-positive thymocytes

myeloid hyperplasia ( J:357366 )

• massive infiltration of myeloid cells in blood, spleen, and lymph nodes

increased neutrophil cell number ( J:357366 )

• tamoxifen-treated mice show 9-fold increase of circulating neutrophils

• tamoxifen-treated mice show increased number of neutrophils in sleep, lymph nodes, and skin

• treatment of tamoxifen-treated mice with a broad-spectrum antibiotics cocktail does not reduce blood neutrophil counts

abnormal spleen morphology ( J:357366 )

• enlarged spleens of tamoxifen-treated mice exhibit a disorganized architecture

• the number of splenic T cells is decreased in young 4-week-old tamoxifen-treated mice, but frequency is not affected

• tamoxifen-treated mice show an increase of neutrophils and S100A8+, S100A9+ and IL-17A+ cells, indicating an infiltration of myeloid cells in the spleen

enlarged spleen ( J:357366 )

• tamoxifen-treated mice exhibit an enlarged spleen as adult mice (> 6 weeks of age)

spleen hypoplasia ( J:357366 )

• tamoxifen-treated mice exhibit reduced spleen cellularity as young 4-week-old mice

decreased spleen B cell follicle number ( J:357366 )

• the number and frequency of splenic B cells is decreased 2-fold in young 4-week-old tamoxifen-treated mice

abnormal spleen marginal zone morphology ( J:357366 )

• enlarged spleens of tamoxifen-treated mice exhibit a disorganized architecture with ill-defined white and red pulp and absence of clear marginal zones surrounding follicles

increased spleen white pulp amount ( J:357366 )

• enlarged spleens of tamoxifen-treated mice exhibit increased area of red pulp

increased IgE level ( J:357366 )

• in tamoxifen-treated mice

immune system

abnormal thymus morphology ( J:357366 )

• trypsin-like and chymotrypsin-like serine protease activities are increased in thymus tissues of tamoxifen-treated mice

• treatment with broad-spectrum antibiotics does not affect serine protease activity in thymus

thymus cortex hypoplasia ( J:357366 )

• thymus cortex area are reduced due to depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

small thymus ( J:357366 )

• thymus size is drastically reduced in tamoxifen-treated mice

thymus atrophy ( J:357366 )

• tamoxifen-treated mice exhibit thymic atrophy characterized by depletion of CD4+CD8+ thymocytes, and increased serine protease activity

• treatment of tamoxifen-treated mice with a broad-spectrum antibiotics cocktail does not reduce thymic atrophy

thymus hypoplasia ( J:357366 )

• thymus cellularity is reduced due to depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

decreased double-positive T cell number ( J:357366 )

• depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

arrested T cell differentiation ( J:357366 )

• thymus shows arrest of thymocyte development at the double positive stage in tamoxifen-treated mice, however the few remaining double positive thymocytes can undergo positive selection as CD4+ or CD8+ single-positive thymocytes

myeloid hyperplasia ( J:357366 )

• massive infiltration of myeloid cells in blood, spleen, and lymph nodes

increased neutrophil cell number ( J:357366 )

• tamoxifen-treated mice show 9-fold increase of circulating neutrophils

• tamoxifen-treated mice show increased number of neutrophils in sleep, lymph nodes, and skin

• treatment of tamoxifen-treated mice with a broad-spectrum antibiotics cocktail does not reduce blood neutrophil counts

abnormal spleen morphology ( J:357366 )

• enlarged spleens of tamoxifen-treated mice exhibit a disorganized architecture

• the number of splenic T cells is decreased in young 4-week-old tamoxifen-treated mice, but frequency is not affected

• tamoxifen-treated mice show an increase of neutrophils and S100A8+, S100A9+ and IL-17A+ cells, indicating an infiltration of myeloid cells in the spleen

enlarged spleen ( J:357366 )

• tamoxifen-treated mice exhibit an enlarged spleen as adult mice (> 6 weeks of age)

spleen hypoplasia ( J:357366 )

• tamoxifen-treated mice exhibit reduced spleen cellularity as young 4-week-old mice

decreased spleen B cell follicle number ( J:357366 )

• the number and frequency of splenic B cells is decreased 2-fold in young 4-week-old tamoxifen-treated mice

abnormal spleen marginal zone morphology ( J:357366 )

• enlarged spleens of tamoxifen-treated mice exhibit a disorganized architecture with ill-defined white and red pulp and absence of clear marginal zones surrounding follicles

increased spleen white pulp amount ( J:357366 )

• enlarged spleens of tamoxifen-treated mice exhibit increased area of red pulp

increased IgE level ( J:357366 )

• in tamoxifen-treated mice

increased chemokine level ( J:357366 )

• the pro-inflammatory cytokine IL-36A is increased 4-fold in the epidermis, IL-24 is increased 15-fold in all epidermal layers , and CXCL3, a chemotactic factor for neutrophils is strongly expressed in immune cells infiltrating the dermis and less weakly in epidermis

abnormal lymph node B cell domain morphology ( J:357366 )

• lymph nodes of tamoxifen-treated mice have increased number of well-defined follicles

abnormal lymph node germinal center morphology ( J:357366 )

• lymph nodes of tamoxifen-treated mice have increased number of germinal centers

enlarged lymph nodes ( J:357366 )

• in tamoxifen-treated mice

lymph node hyperplasia ( J:357366 )

• lymph nodes of tamoxifen-treated mice have increased cellularity

• however, no differences in the frequency or absolute number of B lymphocytes, CD4+ or CD8+ T lymphocytes are seen in the lymph nodes of tamoxifen-treated mice

• lymph nodes of tamoxifen-treated mice show an increased number of neutrophils, S100A8+, S100A9+, and IL17A+ cells

skin inflammation ( J:357366 )

• skin of tamoxifen-treated mice exhibits a 3-fold increase of mast cells, a 9-fold increase of neutrophils, 1.6-fold increase in macrophages, 8.2-fold increase in B cells, 2.5-fold increase in T cells, 3.9-fold increase in IL-17A+ cells and 7.4-fold increase in FOXP3+ cells

• tamoxifen-treated mice show a multiform skin inflammation featured by infiltration of neutrophils, IL-17A+ cells, and B cells, keratinocyte-specific expression of IL-36A and IL-24 cytokines and activated JAK/STAT3 signaling in epidermis and dermis

endocrine/exocrine glands

abnormal thymus morphology ( J:357366 )

• trypsin-like and chymotrypsin-like serine protease activities are increased in thymus tissues of tamoxifen-treated mice

• treatment with broad-spectrum antibiotics does not affect serine protease activity in thymus

thymus cortex hypoplasia ( J:357366 )

• thymus cortex area are reduced due to depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

small thymus ( J:357366 )

• thymus size is drastically reduced in tamoxifen-treated mice

thymus atrophy ( J:357366 )

• tamoxifen-treated mice exhibit thymic atrophy characterized by depletion of CD4+CD8+ thymocytes, and increased serine protease activity

• treatment of tamoxifen-treated mice with a broad-spectrum antibiotics cocktail does not reduce thymic atrophy

thymus hypoplasia ( J:357366 )

• thymus cellularity is reduced due to depletion of CD4+CD8+ double-positive thymocytes in tamoxifen-treated mice

cellular

abnormal keratinocyte differentiation ( J:357366 )

• marker analysis suggests abnormal keratinocyte differentiation in tamoxifen-treated mice

increased keratinocyte proliferation ( J:357366 )

• tamoxifen-treated mice exhibit increased cell proliferation in all basal layer cells and in some suprabasal layer cells of the epidermis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Netherton syndrome		DOID:0050474	OMIM:256500	J:357366