Phenotypes associated with this allele

• Allele Symbol: Crhr2^tm1Klee
• Allele Name: targeted mutation 1, Kuo-Fen Lee
• Allele ID: MGI:2178545
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Crhr2^tm1Klee/Crhr2^tm1Klee	involves: 129S4/SvJae * C57BL/6	MGI:3036169
cx2	Crhr1^tm1Klee/Crhr1^tm1Klee Crhr2^tm1Klee/Crhr2^tm1Klee	involves: 129S4/SvJae * C57BL/6	MGI:3036452

Genotype
MGI:3036169

hm1

• Allelic Composition: Crhr2^tm1Klee/Crhr2^tm1Klee
• Genetic Background: involves: 129S4/SvJae * C57BL/6

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

adipose tissue

decreased total body fat amount ( J:83683 )

• despite a significant increase in food consumption, homozygous mutant mice fed a high-fat diet showed a significant reduction in body fat; the overall end body weight following 16 weeks on a high-fat diet was similar between wild-type and homozygous mutant mice, as mutants displayed increased body water, bone (ash) and muscle (fat-free dry mass (FFDM)-ash) compared with wild-type littermates

• similar changes in body fat and body composition were observed in homozygous mutant mice following repeated cold stress exposure

• however, during 16 weeks on a low-fat diet, homozygous mutant mice displayed normal percentage of body fat compared with wild-type mice

decreased brown fat cell size ( J:83683 )

• homozygous mutant mice exhibited a reduction in BAT cell size

abnormal white fat cell morphology ( J:83683 )

• homozygous mutant mice exhibit a reduction in WAT cell size; adipocytes appeared more rounded with reduced triglyceride stores

abnormal adipose tissue physiology ( J:83683 )

• homozygous mutant mice displayed increased UCP1 levels in brown adipose tissue (BAT), suggesting a possible increase in sympathetic tone

behavior/neurological

abnormal food intake ( J:61484 , J:83683 )

• homozygous male mice exhibited normal basal feeding and weight gain (J:61484)

• homozygous males displayed a decrease in food intake (75% of wild-type food levels) following 24 hrs of food deprivation; however, body weights of mutant and wild-type mice did not differ following food deprivation or re-feeding (J:61484)

• during 16 weeks on a high-fat diet, homozygous mutant mice displayed a significantly higher food consumption than wild-type mice, despite a similar weight gain between the two genotypes (J:83683)

• homozygous mutant mice exposed to repeated cold stress consumed significantly less food than wild-type littermates, during the first half of a 15-day study (J:83683)

• compared with wild-type mice, homozygous mutant mice displayed a lower feed efficiency (gram of weight gained per gram of food consumed) following 16-weeks of high-fat diet; a similar decrease in feed efficiency was observed during the first half of a 15-day cold stress study (J:83683)

• however, during 16 weeks on a low-fat diet, homozygous mutant mice displayed normal food consumption and normal feed efficiency (gram of weight gained per gram of food consumed), compared with wild-type mice (J:83683)

behavioral despair ( J:84341 )

• both male and female homozygous mutant mice displayed a significant increase in immobility, in the modified forced swim test for depression

• female mutant mice exhibited both increased immobility, as well as reduced swimming and climbing time, compared with their wild-type female littermates

• male mutant mice also displayed a significant increase in immobile time and a decrease in swim time, but showed no difference in the amount of time spent climbing compared with wild-type male mice

• homozygous mutant mice exhibited a sexually dichotomous sensitivity, in terms of duration of action, to treatment with the CRHR1 antagonist antalarmin: both males and females displayed a rapid decrease in immobile time after treatment, but the duration of antidepressant action was longer in females

increased anxiety-related response ( J:61484 )

• both male and female mutant mice displayed increased anxiety-like behavior on the elevated plus maze and the open-field test; however, no differences were observed between mutant and wild-type mice in overall locomotor activity in the elevated plus maze, or in anxiety-like behavior measured in the light/dark box experiment

decreased vertical activity ( J:83683 )

• homozygotes displayed slightly decreased rearing counts relative to wild-type controls; however, this trend did not reach statistical significance

• otherwise, homozygotes displayed normal horizontal and vertical locomotor activity levels during either the light or dark cycle

cardiovascular system

abnormal blood vessel morphology ( J:76864 )

increased angiogenesis ( J:76864 )

• at 3 weeks or later, homozygotes exhibit tissue hypervascularization associated with a significant increase in tissue capillaries as well as a profound increase in both the size and number of larger conductance vessels (not observed at E11 or P15)

abnormal systemic arterial blood pressure ( J:61484 )

• i.v. infusion of urocortin resulted in a striking depressor response in blood pressure in control mice but had no effect on mean arterial pressure in mutant mice

• however, homozygotes showed a rapid and robust depressor response to sodium nitroprusside injection, indicating a normal vasodilatory response

hypertension ( J:76864 )

• homozygotes are hypertensive despite a significantly increased vascular surface area

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:61484 )

N • all components of the HPA axis appeared anatomically normal

N • H&E staining revealed no differences in the structure or cell types of the pituitary and adrenal glands; pituitary corticotropes appeared qualitatively normal

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:83683 )

N • homozygous mutant mice and wild-type mice displayed similar body temperatures before or after repeated cold stress exposure

N • following repeated exposure to cold stress, homozygous mutant mice displayed no differences in plasma lipids (cholesterol, triglycerides or free fatty acids)

N • during 16 weeks on a low-fat diet, homozygous mutant mice displayed normal plasma lipids and normal feed efficiency (gram of weight gained per gram of food consumed), compared with wild-type mice

decreased circulating cholesterol level ( J:83683 )

• following 16-weeks of a high-fat diet, homozygotes displayed a significant reduction in plasma cholesterol levels, despite the increased high-fat food intake

decreased circulating free fatty acids level ( J:83683 )

• following 16-weeks of a high-fat diet, homozygotes displayed a significant reduction in free fatty acid levels, despite the increased high-fat food intake

decreased circulating triglyceride level ( J:83683 )

• following 16-weeks of a high-fat diet, homozygotes displayed a significant reduction in plasma triglyceride levels, despite the increased high-fat food intake

abnormal glucose homeostasis ( J:83683 )

• under basal conditions, homozygous mutant mice displayed normal glucose levels

• following glucose challenge, homozygous mutant males displayed lower peak plasma glucose levels compared with wild-type mice; in addition, mutant glucose levels declined at a faster rate

increased insulin sensitivity ( J:83683 )

• under basal conditions, homozygous mutant mice displayed normal insulin levels

• following insulin administration, glucose levels in homozygous mutant mice decreased faster than wild-type levels

• following 4 weeks on a high-fat diet, homozygous mutants displayed no increase in their plasma glucose levels, compared with their baseline, and only a mild increase in their plasma insulin levels, compared with wild-type littermates

abnormal hormone level ( J:61484 )

• homozygous mutant mice displayed normal basal levels of POMC1 (ACTH) and corticosterone

• homozygous mutant mice displayed a hypersensitive HPA axis, with mutant POMC1 (ACTH) and corticosterone levels peaking faster than wild-type levels in response to physical-restraint stress; mutant mice also responded with greater amplitude, with mutant mouse corticosterone levels doubling control levels after 10 min of physical restraint

• in situ hybridization revealed increased CRH (corticotropin releasing hormone) mRNA levels in the central nucleus of the amygdala, as well as increased urocortin mRNA levels in the rostral region of the Edinger-Westphal nucleus

Genotype
MGI:3036452

cx2

• Allelic Composition: Crhr1^tm1Klee/Crhr1^tm1Klee; Crhr2^tm1Klee/Crhr2^tm1Klee
• Genetic Background: involves: 129S4/SvJae * C57BL/6

behavior/neurological

abnormal anxiety-related response ( J:77641 )

• double homozygous mutant mice showed a sexually dichotomous anxiety-like behavior on the elevated plus maze: female double mutant mice displayed anxiolytic-like behavior, whereas male double mutant mice showed significantly increased anxiety-like behavior relative to females

• no significant differences were observed in center visits between female and male double mutant mice in the open-field test; however, female double mutant mice produced significantly fewer fecal boli, suggesting an anxiolytic-like behavior

• notably, the dam's genotype affects the anxiety-like behavior of double mutant males: a pup born to a heterozygous or homozygous mutant dam exhibits significantly increased anxiety-like behavior, regardless of that pup's genotype

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:77641 )

N • histology of the pituitary gland showed no anatomic abnormalities

decreased adrenal gland zona fasciculata size ( J:77641 )

• histologic analysis revealed hypoplasia of the zona fasciculata (corticosterone-producing region) of the adrenal cortex

adrenal gland atrophy ( J:77641 )

• similar to Crhr1^tm1Klee mutant mice, double mutant mice displayed atrophy of the adrenal gland due to agenesis of the adrenal cortex (hypoplasia of the zona fasciculata region)

homeostasis/metabolism

abnormal hormone level ( J:77641 )

• double homozygous mutant mice showed significantly lower basal levels of corticosterone compared to Crhr1^tm1Klee single mutant mice; in contrast, basal levels of POMC1 (ACTH) did not differ between control, Crhr1^tm1Klee single-, Crhr2^tm1Klee single-, and double mutant mice

• double homozygous mutant mice displayed a minimal HPA axis response to physical-restraint stress, with significantly lower POMC1 (ACTH) and corticosterone levels compared to Crhr1^tm1Klee single mutant mice

• CRH mRNA levels were increased in Crhr1^tm1Klee single- and double-mutant mice, and urocortin-3 and arginine vasopressin mRNA levels were increased in Crhr2^tm1Klee single- and double-mutant mice