Pdx1<tm1Macd> Targeted Allele Detail MGI Mouse (MGI:2388676)

Pdx1^tm1Macd
Targeted Allele Detail

Nomenclature

Symbol:	Pdx1^tm1Macd
Name:	pancreatic and duodenal homeobox 1; targeted mutation 1, Raymond J MacDonald
MGI ID:	MGI:2388676
Synonyms:	Pdx1^tTA
Gene:	Pdx1 Location: Chr5:148081702-148087423 bp, + strand Genetic Position: Chr5, 82.0 cM

Mutation
origin

Germline Transmission:	Earliest citation of germline transmission: J:79206
Parent Cell Line:	R1 (ES Cell)
Strain of Origin:	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺

Mutation
description

Allele Type:	Targeted (knock-in)
Mutations:	Insertion, Intragenic deletion
	Exons 1 and 2, which encompass the entire coding region, were replaced with a cassette containing a tetracycline transactivator (tTA) and a neo resistance gene. RT-PCR showed tTA expression in adult pancreas tissue but not in other visceral organs or salivary glands. (J:79206)

Find Mice (IMSR)

Mouse strains and cell lines available from the International Mouse Strain Resource (IMSR)

Carrying this Mutation:	Mouse Strains: 1 strain available Cell Lines: 0 lines available
Carrying any Pdx1 Mutation:	11 strains or lines available

Phenotype
summary

Phenotype Summary by Mammalian Phenotype terms

(show or hide all annotated terms)

Genotypes are listed in the next section.

Key:

hm	homozygous	ht	heterozygous
cn	conditional genotype	cx	complex: > 1 genome feature
tg	involves transgenes	ot	other: hemizygous, indeterminate,...
N	normal phenotype		expected model not found

Affected Systems	Genotypes:	hm1	ht2	cn3	tg4	tg5	tg6	tg7	tg8
cellular								√
increased cell proliferation								√
		hm1	ht2	cn3	tg4	tg5	tg6	tg7	tg8
digestive/alimentary system				√	√	√	√	√	√
digestive/alimentary system phenotype							N
abnormal digestive system morphology							√
abnormal pancreas morphology							√
abnormal pancreas development					√	√	√	√	√
abnormal endocrine pancreas morphology							√
abnormal pancreatic islet morphology				√
abnormal pancreatic beta cell morphology								√
small pancreatic islets								√
pancreatic acinar hypoplasia							√
exocrine pancreas hyperplasia							√
small pancreas							√
absent pancreas									√
abnormal stomach morphology							√
abnormal stomach epithelium morphology							√
increased glucagon secretion								√
decreased insulin secretion								√
		hm1	ht2	cn3	tg4	tg5	tg6	tg7	tg8
endocrine/exocrine glands				√	√	√	√	√	√
abnormal pancreas morphology							√
abnormal pancreas development					√	√	√	√	√
abnormal endocrine pancreas morphology							√
abnormal pancreatic islet morphology				√
abnormal pancreatic beta cell morphology								√
small pancreatic islets								√
pancreatic acinar hypoplasia							√
exocrine pancreas hyperplasia							√
small pancreas							√
absent pancreas									√
increased glucagon secretion								√
decreased insulin secretion								√
		hm1	ht2	cn3	tg4	tg5	tg6	tg7	tg8
homeostasis/metabolism			√					√	√
impaired glucose tolerance			√					√	√
decreased circulating glucose level								√
increased circulating glucose level								√
		hm1	ht2	cn3	tg4	tg5	tg6	tg7	tg8
liver/biliary system		N					N
liver/biliary system phenotype		N					N

Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype	Allelic Composition	Genetic Background
hm1	Pdx1^tm1Macd/Pdx1^tm1Macd	involves: 129S1/Sv * 129X1/SvJ
liver/biliary system liver/biliary system phenotype (J:151981) mice exhibit normal development of the gall bladder, collecting ducts, and common duct
Genotype	Allelic Composition	Genetic Background
ht2	Pdx1^tm1Macd/Pdx1⁺	involves: 129S1/Sv * 129X1/SvJ
homeostasis/metabolism impaired glucose tolerance (J:79206, J:101742) heterozygotes display partially impaired glucose tolerance compared to wild-type mice; doxycycline treatment has no effect (J:79206) heterozygotes display partially impaired early response to glucose challenge compared to wild-type mice; ability to recover after glucose challenge is impaired (J:101742)
Genotype	Allelic Composition	Genetic Background
cn3	Neurog3^{tm1.1(cre/ESR1)Ggu}/Neurog3⁺ Pdx1^tm1Macd/Pdx1⁺ Tg(tetO-Myt1)2Ggu/0	involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ
digestive/alimentary system abnormal pancreatic islet morphology (J:136131) fewer cells are induced to produce glucagons than in Pdx1^tm1Macd/Pdx1⁺ Tg(tetO-Neurog3)8Ggu mice endocrine/exocrine glands abnormal pancreatic islet morphology (J:136131) fewer cells are induced to produce glucagons than in Pdx1^tm1Macd/Pdx1⁺ Tg(tetO-Neurog3)8Ggu mice
Genotype	Allelic Composition	Genetic Background
tg4	Pdx1^tm1Macd/Pdx1⁺ Tg(tetO-Neurog3)8Ggu/0	involves: 129S1/Sv * 129X1/SvJ
digestive/alimentary system abnormal pancreas development (J:136131) epithelial to mesenchyme transition is induced in the pancreas mice exhibit precocious endocrine differentiation, converting nearly all pancreatic cells to glucagon producing cells after E11.5 endocrine/exocrine glands abnormal pancreas development (J:136131) epithelial to mesenchyme transition is induced in the pancreas mice exhibit precocious endocrine differentiation, converting nearly all pancreatic cells to glucagon producing cells after E11.5
Genotype	Allelic Composition	Genetic Background
tg5	Pdx1^tm1Macd/Pdx1⁺ Tg(tetO-Myt1)2Ggu/0	involves: 129S1/Sv * 129X1/SvJ
digestive/alimentary system abnormal pancreas development (J:136131) mice exhibit precocious endocrine differentiation, converting 1.8-fold more pancreatic cells to glucagon producing, immature alpha cells at E11.5 than in Pdx1^tm1Macd heterozygotes however, this conversion is not sustained later in development as E18.5, only rare glucagons producing cells are found endocrine/exocrine glands abnormal pancreas development (J:136131) mice exhibit precocious endocrine differentiation, converting 1.8-fold more pancreatic cells to glucagon producing, immature alpha cells at E11.5 than in Pdx1^tm1Macd heterozygotes however, this conversion is not sustained later in development as E18.5, only rare glucagons producing cells are found
Genotype	Allelic Composition	Genetic Background
tg6	Pdx1^tm1Macd/Pdx1⁺ Tg(tetO-Sox17,-EGFP)1Jaw/0	involves: 129S1/Sv * 129X1/SvJ
digestive/alimentary system digestive/alimentary phenotype (J:151981) when treated with doxycycline until E12.5, mice exhibit normal no ectopic mass at the pyloric-duodenum junction abnormal digestive system morphology (J:151981) at E16.5, mice exhibit a large mass at the pyloric junction between the stomach and duodenum unlike in control mice at E16.5, mice exhibit many ectopic duct-like structures unlike in control mice abnormal pancreas morphology (J:151981) when treated with doxycycline until E12.5, endocrine cells are replaced with ductal cells unlike in control mice abnormal pancreas development (J:151981) at E10.5, the remnant of the dorsal and ventral pancreatic bud is fused to the gut tube unlike in control mice abnormal endocrine pancreas morphology (J:151981) at 6 weeks, mature endocrine cells are nearly absent in mice treated with doxycycline until E12.5 unlike in control mice pancreatic acinar hypoplasia (J:151981) at 6 weeks, in mice treated with doxycycline until E12.5 exocrine pancreas hyperplasia (J:151981) at 6 weeks, mice treated with doxycycline until E12.5 exhibit a massive expansion of ductal tissues compared to in control mice small pancreas (J:151981) at E16.5, only a pancreatic remnant remains abnormal stomach morphology (J:151981) at E16.5, mice exhibit hyperplastic stomach epithelium and mesenchyme unlike in control mice abnormal stomach epithelium morphology (J:151981) hyperplastic at E16.5 endocrine/exocrine glands abnormal pancreas morphology (J:151981) when treated with doxycycline until E12.5, endocrine cells are replaced with ductal cells unlike in control mice abnormal pancreas development (J:151981) at E10.5, the remnant of the dorsal and ventral pancreatic bud is fused to the gut tube unlike in control mice abnormal endocrine pancreas morphology (J:151981) at 6 weeks, mature endocrine cells are nearly absent in mice treated with doxycycline until E12.5 unlike in control mice pancreatic acinar hypoplasia (J:151981) at 6 weeks, in mice treated with doxycycline until E12.5 exocrine pancreas hyperplasia (J:151981) at 6 weeks, mice treated with doxycycline until E12.5 exhibit a massive expansion of ductal tissues compared to in control mice small pancreas (J:151981) at E16.5, only a pancreatic remnant remains liver/biliary system liver/biliary system phenotype (J:151981) liver bud development and biliary epithelium are normal
Genotype	Allelic Composition	Genetic Background
tg7	Pdx1^tm1Macd/Pdx1^tm1Macd Tg(tetO-Ipf1,EGFP)956.6Macd/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
homeostasis/metabolism decreased circulating glucose level (J:101742) 14 days after doxycycline withdrawal after 14 days of treatment resulted in a significant decrease in blood glucose levels with 4/5 mice becoming normoglycemic by 28 days increased circulating glucose level (J:79206) with doxycycline treatment for 21 day, adult rescue mice show a 4-fold increase in fasting blood glucose to diabetic levels impaired glucose tolerance (J:79206, J:101742) adult transgenic rescue animals treated with doxycycline for 14 days exhibit a defective response to glucose challenge compared to wild-type, non mutant transgenic, or untreated rescue mice (J:79206) when adult mice are treated with doxycycline for 0, 7, 14, or 21 days, mice show an increased early glucose response within 7 days of start of treatment and ability to recover from glucose challenge is impaired compared to untreated transgenics where glucose levels recover to basal levels within 3 hours; by 14 days of doxycycline treatment, mice have diabetes (J:101742) endocrine/exocrine glands abnormal pancreas development (J:79206) pancreas of transgenic rescue newborn mice is 50% the size of a normal wild-type neonatal pancreas treatment of pregnant mice with doxycycline from the first day of pregnancy through parturition prevents formation of the pancreas in mice with the transgenic rescue genotype treatment on E11.5 arrests pancreatic development ~36 hours later; at birth the underdeveloped remnant consisted of a large and extended duct with several terminal, aborted, ductal buds with ducts lined with a single layer of primitive epithelial cells and with no acinar or islet tissue abnormal pancreatic beta cell morphology (J:101742) after 14 or 28 days of dox treatment there are, still present, beta cells which lack insulin small pancreatic islets (J:101742) after dox treatment for 14 days, there is a significant decrease in islet area compared to wild-type increased glucagon secretion (J:101742) in doxycycline-treated mice there is an increase in glucagons-positive cells decreased insulin secretion (J:101742) there is a marked reduction in insulin in pancreata of doxycycline-treated mice; after withdrawal of doxycycline, insulin +ve cells are detected in islets of smaller islet-like cell clusters digestive/alimentary system abnormal pancreas development (J:79206) pancreas of transgenic rescue newborn mice is 50% the size of a normal wild-type neonatal pancreas treatment of pregnant mice with doxycycline from the first day of pregnancy through parturition prevents formation of the pancreas in mice with the transgenic rescue genotype treatment on E11.5 arrests pancreatic development ~36 hours later; at birth the underdeveloped remnant consisted of a large and extended duct with several terminal, aborted, ductal buds with ducts lined with a single layer of primitive epithelial cells and with no acinar or islet tissue abnormal pancreatic beta cell morphology (J:101742) after 14 or 28 days of dox treatment there are, still present, beta cells which lack insulin small pancreatic islets (J:101742) after dox treatment for 14 days, there is a significant decrease in islet area compared to wild-type increased glucagon secretion (J:101742) in doxycycline-treated mice there is an increase in glucagons-positive cells decreased insulin secretion (J:101742) there is a marked reduction in insulin in pancreata of doxycycline-treated mice; after withdrawal of doxycycline, insulin +ve cells are detected in islets of smaller islet-like cell clusters cellular increased cell proliferation (J:101742) foci of duct proliferation are present in mice after 14 days of doxycycline treatment and become more prominent with continued treatment
Genotype	Allelic Composition	Genetic Background
tg8	Pdx1^tm1Macd/Pdx1^tm1Macd Tg(tetO-Ipf1,lacZ)958.1Macd/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
homeostasis/metabolism impaired glucose tolerance (J:103522) transgenic mice gradually attain an impaired glucose tolerance response to glucose challenge endocrine/exocrine glands abnormal pancreas development (J:103522) when dams are treated with doxycycline from conception through birth, only small epithelial remnants of the pancreas form; treatment at E7.5 or E8.5 results in the same phenotype doxycycline from E9.5 diminishes epithelial morphogenesis; treatement from E9.5 allows outgrowth of a linear epithelial tube with nascent invaginations representing initial primary branching treatment from E11.5 allows the formation of a larger crude duct-like structure with a few distal primary branches; treatement from E12.5 permits formation of extensive fine structure consisting of immature acini and associated small ductules with treatment from E12.5, pancreatic dorsal and ventral remnants composed of convoluted partially branched duct-like epithelium of columnar epithelium are present, and show a block at the stage of acinar cell formation examination of embryo ductal remnants from mice treated with dox from E11.5 show an absence of preacini; treatment from E12.5 results in a larger remnant with a smaller proportion of primitive duct; the epithelium is replaced by numerous eosinophilic clusters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini absent pancreas (J:103522) ~1/5 pups are born without a pancreas; rescue of pancreas formation is observed in ~80% of transgenic mice digestive/alimentary system abnormal pancreas development (J:103522) when dams are treated with doxycycline from conception through birth, only small epithelial remnants of the pancreas form; treatment at E7.5 or E8.5 results in the same phenotype doxycycline from E9.5 diminishes epithelial morphogenesis; treatement from E9.5 allows outgrowth of a linear epithelial tube with nascent invaginations representing initial primary branching treatment from E11.5 allows the formation of a larger crude duct-like structure with a few distal primary branches; treatement from E12.5 permits formation of extensive fine structure consisting of immature acini and associated small ductules with treatment from E12.5, pancreatic dorsal and ventral remnants composed of convoluted partially branched duct-like epithelium of columnar epithelium are present, and show a block at the stage of acinar cell formation examination of embryo ductal remnants from mice treated with dox from E11.5 show an absence of preacini; treatment from E12.5 results in a larger remnant with a smaller proportion of primitive duct; the epithelium is replaced by numerous eosinophilic clusters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini absent pancreas (J:103522) ~1/5 pups are born without a pancreas; rescue of pancreas formation is observed in ~80% of transgenic mice

References

Original:	J:79206 Holland AM et al., "Experimental control of pancreatic development and maintenance." Proc Natl Acad Sci U S A 2002 Sep 17;99(19):12236-41
All:	11 reference(s)

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