Phenotypes associated with this allele

• Allele Symbol: Ptx3^tm1Mant
• Allele Name: targeted mutation 1, Alberto Mantovani
• Allele ID: MGI:2675283
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Ptx3^tm1Mant/Ptx3^tm1Mant	either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)	MGI:2675289
hm2	Ptx3^tm1Mant/Ptx3^tm1Mant	involves: 129 * C57BL/6J	MGI:3838858
hm3	Ptx3^tm1Mant/Ptx3^tm1Mant	involves: 129S1/Sv * 129X1/SvJ	MGI:3838857

Genotype
MGI:2675289

hm1

• Allelic Composition: Ptx3^tm1Mant/Ptx3^tm1Mant
• Genetic Background: either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)

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

immune system

abnormal T-helper 1 physiology ( J:85080 )

• upon challenge with Aspergillus fumigatus, homozygotes fail to develop an appropriate T_H1-type response and display a cytokine profile skewed towards a T_H2-type response, as revealed by reduced IFN-gamma and IL-12 levels and increased IL-4 levels in mutant lungs

abnormal professional antigen presenting cell physiology ( J:85080 )

• homozygotes display defective recognition of Aspergillus fumigatus conidia by alveolar macrophages and dendritic cells

abnormal macrophage physiology ( J:85080 )

• homozygotes exhibit defective recognition of Aspergillus fumigatus conidia by alveolar macrophages

impaired macrophage phagocytosis ( J:85080 )

• in vitro, the ability of mutant alveolar macrophages to ingest and kill resting Aspergillus fumigatus conidia is impaired relative to wild-type macrophages

abnormal dendritic cell physiology ( J:85080 )

• homozygotes exhibit defective recognition of Aspergillus fumigatus conidia by dendritic cells

• activation by interaction with conidia, assessed as production of IL-12, and upregulation of MHC II and CD86 antigens, is impaired in lung dendritic cells from A. fumigatus infected homozygotes

• addition of PTX3 fully restores the ability of mutant dendritic cells to respond to conidia

lung inflammation ( J:85080 )

• lungs from Aspergillus fumigatus infected homozygotes display a massive inflammatory response, the presence of hyphae and numerous, mostly extracellular, conidia, relative to similarly infected wild-type controls

increased susceptibility to bacterial infection ( J:85080 )

• homozygotes display accelerated death following intratracheal challenge with Pseudomonas aeruginosa, showing a 10-fold increase in lung CFU counts at 24 hrs post-infection relative to wild-type control mice

• in contrast, susceptibility to Listeria monocytogenes and to intra-abdominal sepsis induced by cecal ligation and puncture remain normal

increased susceptibility to fungal infection ( J:85080 )

• homozygotes exhibit increased susceptibility to invasive pulmonary aspergillosis (IPA), with a median survival time of 3 days, and a significant increase in lung and brain colonization; in contrast, all wild-type control mice survive infection

• in an IPA model of allogeneic, T-cell-depleted bone marrow transplantation, combined systemic and local PTX3 administration results in a 2-fold increase in survival time with 2 of 8 homozygotes being cured, along with a >4-fold reduction in lung CFU counts

reproductive system

reduced female fertility ( J:85080 )

♀ • homozygotes display a severe defect in female fertility

respiratory system

lung inflammation ( J:85080 )

• lungs from Aspergillus fumigatus infected homozygotes display a massive inflammatory response, the presence of hyphae and numerous, mostly extracellular, conidia, relative to similarly infected wild-type controls

hematopoietic system

abnormal T-helper 1 physiology ( J:85080 )

• upon challenge with Aspergillus fumigatus, homozygotes fail to develop an appropriate T_H1-type response and display a cytokine profile skewed towards a T_H2-type response, as revealed by reduced IFN-gamma and IL-12 levels and increased IL-4 levels in mutant lungs

abnormal macrophage physiology ( J:85080 )

• homozygotes exhibit defective recognition of Aspergillus fumigatus conidia by alveolar macrophages

impaired macrophage phagocytosis ( J:85080 )

• in vitro, the ability of mutant alveolar macrophages to ingest and kill resting Aspergillus fumigatus conidia is impaired relative to wild-type macrophages

cellular

impaired macrophage phagocytosis ( J:85080 )

• in vitro, the ability of mutant alveolar macrophages to ingest and kill resting Aspergillus fumigatus conidia is impaired relative to wild-type macrophages

Genotype
MGI:3838858

hm2

• Allelic Composition: Ptx3^tm1Mant/Ptx3^tm1Mant
• Genetic Background: involves: 129 * C57BL/6J

reproductive system

reduced female fertility ( J:91829 )

♀ • Background Sensitivity: female homozygotes on a mixed 129/Sv x C57BL/6J genetic background are severely subfertile exhibiting occasional pregnancies, whereas female homozygotes on an inbred 129/Sv genetic background are completely sterile

decreased litter size ( J:91829 )

• only 4 out of 10 female homozygotes become pregnant over a 2-month period producing 1-2 pups/mother versus a mean of one pregnancy per month with a mean of 9 pups/mother in wild-type females

Genotype
MGI:3838857

hm3

• Allelic Composition: Ptx3^tm1Mant/Ptx3^tm1Mant
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

reproductive system

reproductive system phenotype ( J:91829 )

♀N • female homozygotes show a normal ovulation rate with a similar number of oocytes at day 0.5 after natural mating, or at 14 hrs after hCG injection relative to heterozygous controls

♀N • no defects in implantation, embryo development or delivery are observed upon transfer of wild-type blastocysts to the uterus of pseudopregnant female homozygotes

abnormal cumulus oophorus morphology ( J:91829 )

♀ • mutant corona radiata cells do not polarize and cumulus cells fail to radiate out from a central oocyte as in wild-type preovulatory follicles

♀ • at 14 hrs after hCG injection, mutant oocytes are still associated with cumulus cells; however, mutant cumuli appear disorganized, with cumulus cells uniformly dispersed in the cumulus mass and the oocytes randomly located

absent cumulus expansion ( J:91829 , J:126717 )

♀ • a few hours before ovulation, cumulus cells fail to acquire a polarized and elongated shape during deposition of the viscoelastic extracellular matrix (cumulus expansion) and cumulus cell layers appear disorganized (J:91829)

♀ • in vitro, the mutant viscoelastic matrix is unstable and spontaneously dissolves within 15-60 min versus several hours in wild-type cumuli, leading to rapid oocyte denudation (J:91829)

♀ • in vivo, mutant cumuli become dissociated after ovulation (at 20 hrs after hCG) with cumulus cells and oocytes dispersed into the oviduct, instead of being arranged around the oocyte as in control cumuli (J:91829)

♀ • at 16 hrs of culture in the presence of FSH and fetal bovine serum (FBS), cumuli isolated from PMSG-primed homozygotes synthesize normal amounts of hyaluronan (HA), but are unable to organize it in a stable matrix, as shown by the release of HA in the medium and dispersion of cumulus cells; however, exogenous PTX3 restores a normal cumulus phenotype in a dose-dependent fashion (J:91829)

♀ • importantly, covalent linkage of serum-derived inter-alpha-trypsin inhibitor (IalphaI) heavy chains to HA occurs normally in the cumulus matrix of mutant female mice (J:91829)

♀ • in vitro, purified human recombinant PTX3 allows the formation and expansion of extracellular matrix by mutant mouse cumulus-oocyte complexes (COCs) (J:126717)

♀ • human recombinant PTX3-specific N-terminal region, but not the PTX3-pentraxin C-terminal domain, shows the same ability as full-length protein to bind to heavy chains (HCs) of IalphaI and enable HA organization and matrix formation by mutant COCs (J:126717)

♀ • MNB4, a monoclonal antibody raised against PTX3 N terminus which blocks the PTX3/IalphaI interaction, prevents recombinant full-length PTX3 from restoring a normal phenotype to mutant COCs (J:126717)

female infertility ( J:91829 )

♀ • Background Sensitivity: female homozygotes on an inbred 129/Sv genetic background are sterile, whereas female homozygotes on a mixed 129/Sv x C57BL/6J genetic background are severely subfertile

impaired fertilization ( J:91829 )

♀ • in vivo, oocytes from both spontaneously ovulating or superovulated female homozygotes fail to reach the 2-cell stage (day 1.5); however, oocyte meiotic maturation appears unaffected, as revealed by a normal % of oocytes showing the first polar body

♀ • however, oocytes ovulated by female homozygotes can be fertilized in vitro, indicating that abnormal cumulus expansion is the major cause for in vivo fertilization failure

endocrine/exocrine glands

abnormal cumulus oophorus morphology ( J:91829 )

♀ • mutant corona radiata cells do not polarize and cumulus cells fail to radiate out from a central oocyte as in wild-type preovulatory follicles

♀ • at 14 hrs after hCG injection, mutant oocytes are still associated with cumulus cells; however, mutant cumuli appear disorganized, with cumulus cells uniformly dispersed in the cumulus mass and the oocytes randomly located

absent cumulus expansion ( J:91829 , J:126717 )

♀ • a few hours before ovulation, cumulus cells fail to acquire a polarized and elongated shape during deposition of the viscoelastic extracellular matrix (cumulus expansion) and cumulus cell layers appear disorganized (J:91829)

♀ • in vitro, the mutant viscoelastic matrix is unstable and spontaneously dissolves within 15-60 min versus several hours in wild-type cumuli, leading to rapid oocyte denudation (J:91829)

♀ • in vivo, mutant cumuli become dissociated after ovulation (at 20 hrs after hCG) with cumulus cells and oocytes dispersed into the oviduct, instead of being arranged around the oocyte as in control cumuli (J:91829)

♀ • at 16 hrs of culture in the presence of FSH and fetal bovine serum (FBS), cumuli isolated from PMSG-primed homozygotes synthesize normal amounts of hyaluronan (HA), but are unable to organize it in a stable matrix, as shown by the release of HA in the medium and dispersion of cumulus cells; however, exogenous PTX3 restores a normal cumulus phenotype in a dose-dependent fashion (J:91829)

♀ • importantly, covalent linkage of serum-derived inter-alpha-trypsin inhibitor (IalphaI) heavy chains to HA occurs normally in the cumulus matrix of mutant female mice (J:91829)

♀ • in vitro, purified human recombinant PTX3 allows the formation and expansion of extracellular matrix by mutant mouse cumulus-oocyte complexes (COCs) (J:126717)

♀ • human recombinant PTX3-specific N-terminal region, but not the PTX3-pentraxin C-terminal domain, shows the same ability as full-length protein to bind to heavy chains (HCs) of IalphaI and enable HA organization and matrix formation by mutant COCs (J:126717)

♀ • MNB4, a monoclonal antibody raised against PTX3 N terminus which blocks the PTX3/IalphaI interaction, prevents recombinant full-length PTX3 from restoring a normal phenotype to mutant COCs (J:126717)