Phenotypes associated with this allele

• Allele Symbol: Nkx2-1^tm2Shk
• Allele Name: targeted mutation 2, Shioko Kimura
• Allele ID: MGI:3653645
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nkx2-1^tm2Shk/Nkx2-1^tm2Shk	involves: 129S4/SvJae * 129X1/SvJ	MGI:3653706
cn2	Nkx2-1^tm2Shk/Nkx2-1^tm2Shk Tg(Syn1-cre)671Jxm/0	involves: 129X1/SvJ * C57BL/6 * CBA	MGI:4367245
cn3	Nkx2-1^tm2Shk/Nkx2-1^tm2Shk Tg(TPO-cre)1Shk/0	involves: 129X1/SvJ * FVB/NCr	MGI:3653705

Genotype
MGI:3653706

hm1

• Allelic Composition: Nkx2-1^tm2Shk/Nkx2-1^tm2Shk
• Genetic Background: involves: 129S4/SvJae * 129X1/SvJ

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

endocrine/exocrine glands

abnormal thyroid follicle morphology ( J:111027 )

• thyroids have a disordered follicle architecture more noticeable with age compared to control Titf1^tm2Shk homozygotes

• cultured follicular cells form irregular-shaped polygonal structures lacking colloid accumulation compared to mature, spherical colloid-containing follicles formed by cells from Titf1^tm2Shk homozygotes

homeostasis/metabolism

increased circulating thyroid-stimulating hormone level ( J:111027 )

• mean serum TSH levels are higher than in Titf1^tm2Shk homozygous mice but statistical significance was not obtained

Genotype
MGI:4367245

cn2

• Allelic Composition: Nkx2-1^tm2Shk/Nkx2-1^tm2Shk; Tg(Syn1-cre)671Jxm/0
• Genetic Background: involves: 129X1/SvJ * C57BL/6 * CBA

mortality/aging

early reproductive senescence ( J:116686 )

♀ • female mutants exhibit a shorter reproductive span than control females, with 50% of mutant dams ceasing to deliver pups by 6-9 months of age

reproductive system

early reproductive senescence ( J:116686 )

♀ • female mutants exhibit a shorter reproductive span than control females, with 50% of mutant dams ceasing to deliver pups by 6-9 months of age

delayed sexual maturation ( J:116686 )

♀ • female mutants display delayed puberty, defined as the age at which the first ovulation takes place, relative to control females

♀ • however, the onset of vaginal opening is normal relative to control littemates

♀ • reproductive defects are associated with reduced hypothalamic expression of genes critical for sexual development and deregulation of a gene involved in restraining puberty

delayed estrous cycle ( J:116686 )

♀ • however, no differences in body weight gain are observed over a 240-day period relative to control females

♀ • female mutants show a significantly delayed initiation of cyclicity relative to control females

abnormal ovulation ( J:116686 )

♀ • female mutants deliver their first litter ~2 weeks later than control females, consistent with a 10-day delay in first ovulation assessed by the age at first estrus

♀ • however, mating behavior appears unaffected

prolonged estrous cycle ( J:116686 )

♀ • the length of the first estrous cycle is nearly three times longer than in wild-type controls

♀ • subsequent estrous cycles are slightly longer in duration (5-6 days) relative to cycles in control littermates (4-5 days)

reduced female fertility ( J:116686 )

♀ • 50% of female mutants fail to become pregnant by 6-9 months of age, whereas >90% of control females reproduce normally at this age

♀ • mutant dams produce fewer pups than control dams in a 1-year period

♀ • the total number of litters produced by each mutant dam every 90 days is reduced by ~50% by 3 months of age

♀ • however, pups born to mutant females appear normal and show normal birth weights relative to controls

behavior/neurological

behavior/neurological phenotype ( J:116686 )

N • adult mutant exhibit normal novel object recognition as well as normal learning and memory, as assessed by the water maze and passive avoidance tests, indicating that basal forebrain cholinergic neuronal function is essentially intact

decreased exploration in new environment ( J:116686 )

• adult mutants exhibit reduced novel location recognition relative to wild-type mice

• however, novel object recognition remains intact relative to wild-type mice

increased anxiety-related response ( J:116686 )

• unexpectedly, adult mutants display higher, instead of lower, measures of anxiety than wild-type mice in the elevated zero maze test

enhanced coordination ( J:116686 )

• at 14 months of age, adult mutants are able to stay longer on the rotarod than wild-type mice

increased locomotor activity ( J:116686 )

• unexpectedly, adult mutants exhibit higher, rather than lower, locomotor activity than age-matched wild-type controls in the open field test

nervous system

nervous system phenotype ( J:116686 )

N • mutants display normal basal ganglia/hypothalamic morphology relative to control littermates

N • no extrapyramidal deficits associated with basal ganglia dysfunction are observed

Genotype
MGI:3653705

cn3

• Allelic Composition: Nkx2-1^tm2Shk/Nkx2-1^tm2Shk; Tg(TPO-cre)1Shk/0
• Genetic Background: involves: 129X1/SvJ * FVB/NCr

endocrine/exocrine glands

abnormal thyroid follicle morphology ( J:111027 )

• glands consist mostly of atrophic or degenerative follicles, and multiple smaller follicles lined by cuboidal to columnar epithelial cells in various ratios; atrophic/degenerative follicles had various sizes and shapes and are lined with flattened to cuboidal epithelial cells

• colloid in the lumen of cells in these follicles is partially or almost completely depleted

• most of these cells have lost Titf1 expression

• space between normal and atrophic/degenerative follicles is filled with small follicles resembling hyperplastic thyroid follicles containing little or no colloid in their lumens

• cultured follicular cells form irregular-shaped polygonal structures lacking colloid accumulation compared to mature, spherical colloid-containing follicles formed by cells from Titf1^tm2Shk homozygotes

small thyroid gland ( J:111027 )

• mice expressing highly elevated TSH levels have the most severely affected throid glands; size of thyroid glands is reduced to about half the diameter of control thyroid glands

homeostasis/metabolism

increased circulating thyroid-stimulating hormone level ( J:111027 )

• mean serum TSH levels are higher than in Titf1^tm1Shk/ Titf1^tm2Shk mice or Titf1^tm2Shk homozygous mice but statistical significance was not obtained

• extremely high TSH serum levels are sporadically observed

neoplasm

increased adenoma incidence ( J:111027 )

• small follicles between normal and atrophic/degenerative follicles occasionally form nodular lesions considered to be follicular adenoma