STOCK Pcsk1^tm1Dfs/J

Stock number: 006327
Product name: PC1/3 KO
Strain synonyms: PC1/3 null
Research areas: Diabetes and Obesity Research, Endocrine Deficiency Research, Metabolism Research, Neurobiology Research

Description

These mice lack mature growth hormone-releasing hormone (GHRH), have low pituitary growth hormone, and reduced hepatic insulin-like growth factor-1 mRNA levels. Phenotypically they resemble the “little” mouse that has a mutant GHRH receptor. Insulin producing beta islet cells from homozygotes exhibit abnormal morphology and contain almost no mature insulin.

Detailed description

Mice that are heterozygous for the targeted mutation are viable and fertile. No gene product (mRNA or protein) is detected in the homozygotes by Northern blot analysis of hypothalamic tissue or Western blot analysis of pituitary and brain tissue. Homozygote mice experience perinatal lethality, as the number of homozygotes born is less than the expected Mendelian ratio, and high postnatal lethality. By postnatal day 3, homozygotes are smaller in size than littermates. By 6 weeks of age, the surviving homozygotes are approximately 60% of wildtype body weight. Homozygotes have chronic mild diarrhea with bulky moist stools. Pituitary growth hormone transcript levels are only 25-20% of normal levels. Somatotroph cells in the anterior pituitary are reduced in size and inactive. Insulin-like growth factor 1 serum levels are significantly reduced. Transcript (mRNA) levels are greatly increased for growth hormone-releasing hormone in the hypothalamus and proopiomelanocortin in the pituitary. Mature growth hormone releasing hormone levels are significantly reduced. Mature adrenocorticotropic hormone is not detected in the pituitary, although plasma corticosterone levels are normal. Glucagon–like peptide 1 and 2 are not detectable in the small intestine of homozygotes. Insulin producing beta islet cells from homozygotes exhibit abnormal m orphology and contain almost no mature insulin. Homozygotes exhibit hyperproinsulinenia but have normal glucose tolerance. Immunureactive mature Met-enkephalin and neuropeptide precursor VGF are reduced in brain tissue of homozygous animals. Heterozygotes are mildly obese, have a twofold increase in proinsulin levels in the pancreas and have a lengthened glycemic reponse to the glucose tolerance test. This mutant mouse strain may be useful in studies of neuroendocrine and neuropeptide processing, endocrine and metabolic defects and obesity without diabetes.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 1 and upstream promoter elements. The construct was electroporated into 129X1/SvJ derived GSI-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting male chimeric animals were crossed to C57BL/6J female mice, and then crossed to CD1 outbred mice.

Allele

Symbol: Pcsk1^tm1Dfs
Name: targeted mutation 1, Donald F Steiner
MGI accession ID: MGI:2384741
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Pcsk1
Marker name: proprotein convertase subtilisin/kexin type 1
Chromosome: 13
Strain of origin: 129
Molecular note: Exon 1 and several putative transcription control elements were replaced with a neomycin selection cassette. The absence of transcript and protein in homozygous mutant mice was determined by Northern and Western blot analyses.