Phenotypes associated with this allele

• Allele Symbol: Gfra1^tm1Jmi
• Allele Name: targeted mutation 1, Jeffrey Milbrandt
• Allele ID: MGI:1926439
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Gfra1^tm1Jmi/Gfra1^tm1Jmi	involves: 129X1/SvJ * C57BL/6	MGI:2175040
ht2	Gfra1^tm1Jmi/Gfra1^+	involves: 129X1/SvJ * C57BL/6	MGI:2175041
cn3	Gfra1^tm1Jmi/Gfra1^tm2Jmi Tg(CAG-cre/Esr1*)5Amc/0	involves: 129/Sv * C57BL/6 * CBA * SJL	MGI:3715267

Genotype
MGI:2175040

hm1

• Allelic Composition: Gfra1^tm1Jmi/Gfra1^tm1Jmi
• Genetic Background: involves: 129X1/SvJ * C57BL/6

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

mortality/aging

neonatal lethality, complete penetrance ( J:49471 )

• die within 24 hours of birth

renal/urinary system

abnormal kidney morphology ( J:49471 )

• kidney rudiments show severe dysplasia, with disorganized distribution of small numbers of nephron components, including the proximal and distal convoluted tubules, glomeruli, and blood vessels

absent kidney ( J:49471 )

• most homozygotes lack both kidneys, however some show unilateral or bilateral renal dysgenesis

abnormal urinary bladder morphology ( J:49471 )

• newborns have empty bladders with a thickened wall

abnormal ureteric bud morphology ( J:49471 )

• formation of ureteric bud is disrupted in E11.5 embryos

abnormal ureteric bud invasion ( J:49471 )

• penetration of the metanephric mesenchyme by the ureteric bud is disrupted in E11.5 embryos and leads to a failure of mesenchymal tissue condensation

nervous system

abnormal enteric nervous system morphology ( J:49471 )

• the stomach shows a reduction in enteric nervous system plexus density

abnormal enteric ganglia morphology ( J:49471 )

• enteric ganglion cells are absent in the small and large intestine but are present in the esophagus and stomach

• ganglion cells in the stomach are dramatically reduced in number

• no ganglion cells are seen in the ileum and colon, although large nerve fibers extending proximally from the distal colon are apparent

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Hirschsprung's disease		DOID:10487	OMIM:600156 OMIM:606874 OMIM:606875 OMIM:608462 OMIM:611644	J:49471

Genotype
MGI:2175041

ht2

• Allelic Composition: Gfra1^tm1Jmi/Gfra1⁺
• Genetic Background: involves: 129X1/SvJ * C57BL/6

digestive/alimentary system

intestinal hypoperistalsis ( J:82456 )

• decrease in both longitudinal and circular muscle contraction of the intestine in response to electric field stimulation

nervous system

abnormal enteric neuron morphology ( J:82456 )

• neuronal cell size is reduced by 19% in colon submucosal neurons, by 20% in colonic myenteric neurons and by 31% in small bowel myenteric neurons, however the number of myenteric and submucosal neurons in the small bowel and colon are normal

• myenteric neuron acetylcholinesterase-stained fiber counts are reduced by 11% in the small bowel and by 12% in the colon

abnormal neurotransmitter secretion ( J:82456 )

• 70-95% reduction in substance P and VIP release

integument

accelerated hair follicle regression ( J:65034 )

• exhibit accelerated catagen development, with a significant decline in the percentage of catagen II hair follicles and an increase of catagen V-VI hair follicles at P17

thin skin ( J:65034 )

• seen at P17

muscle

intestinal hypoperistalsis ( J:82456 )

• decrease in both longitudinal and circular muscle contraction of the intestine in response to electric field stimulation

Genotype
MGI:3715267

cn3

• Allelic Composition: Gfra1^tm1Jmi/Gfra1^tm2Jmi; Tg(CAG-cre/Esr1*)5Amc/0
• Genetic Background: involves: 129/Sv * C57BL/6 * CBA * SJL

nervous system

nervous system phenotype ( J:122607 )

N • with 4-OHT treatment on E13.5 rather than E15.5, complete loss of enteric neurons in colon is still observed at E18.5, but no abnormalities in enteric ganglia of small intestine is seen

abnormal neuronal precursor proliferation ( J:122607 )

• fewer ENS progenitors are proliferating in the midgut at E13.5 in embryos treated with 4-OHT at E11.5 (12.2% vs 24% in controls)

abnormal enteric nervous system morphology ( J:122607 )

abnormal enteric ganglia morphology ( J:122607 )

• at E18.5, ganglion structure and innervation in the colon is completely disrupted relative to control mice with 4-OHT treatement at E15.5

• enteric ganglion cells die within 36 hours after 4-OHT treatment

absent enteric neurons ( J:122607 )

• with 4-OHT treatment on E15.5, enteric ganglia and neurons are lost in the colon by birth

abnormal nervous system development ( J:122607 )

• abnormal thick nerve bundles are observed in the colons of E18.5 embryos after 4-hydroxytamoxifen, 4-OHT treatment on E15.5; this are likely un-defasciculated extrinsic nerve fibers

cellular

abnormal cell nucleus morphology ( J:122607 )

• nuclei of dying ganglion cells in mutants display numerous indentations in nuclear membrane, some with abnormal constriction of the nuclear membrane resulting in multilobation of the nuclei

• cells are shrunken with condensation of marginal heterochromatin and chromatin masses dispersed in the karyoplasms; diminuition of the cytoplasm and heterochromatin condensation in the nuclei are enhanced in ganglion cells in the myenteric layer

abnormal cell death ( J:122607 )

• enteric ganglion cells die within 36 hours of Gfra1 inactivation induced by 4-OHT treatment of pregnant females, but cell death is by mechanism other than apoptosis; enteric neuron death is not dependent on caspases or Bax

• some cells contain autolysosomes; almost no autophagosomes are detected in mutants at any stage of cell death

abnormal neuronal precursor proliferation ( J:122607 )

• fewer ENS progenitors are proliferating in the midgut at E13.5 in embryos treated with 4-OHT at E11.5 (12.2% vs 24% in controls)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Hirschsprung's disease		DOID:10487	OMIM:600156 OMIM:606874 OMIM:606875 OMIM:608462 OMIM:611644	J:122607