Phenotypes associated with this allele

• Allele Symbol: Tlx3^tm1Sjk
• Allele Name: targeted mutation 1, Stanley J Korsmeyer
• Allele ID: MGI:2180105
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tlx3^tm1Sjk/Tlx3^tm1Sjk	involves: 129S1/Sv	MGI:3773049
hm2	Tlx3^tm1Sjk/Tlx3^tm1Sjk	involves: 129X1/SvJ	MGI:2669096
cx3	Lbx1^tm1Gld/Lbx1^tm1Gld Tlx3^tm1Sjk/Tlx3^tm1Sjk	involves: 129S1/Sv * 129X1/SvJ	MGI:3773047
cx4	Tlx1^tm1Sjk/Tlx1^tm1Sjk Tlx3^tm1Sjk/Tlx3^tm1Sjk	involves: 129S2/SvPas * 129X1/SvJ	MGI:3807393

Genotype
MGI:3773049

hm1

• Allelic Composition: Tlx3^tm1Sjk/Tlx3^tm1Sjk
• Genetic Background: involves: 129S1/Sv

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

nervous system

abnormal glutaminergic neuron morphology ( J:102513 )

• in dorsal horn, glutaminergic differentiation is almost completely abolished compared to wild-type

Genotype
MGI:2669096

hm2

• Allelic Composition: Tlx3^tm1Sjk/Tlx3^tm1Sjk
• Genetic Background: involves: 129X1/SvJ

mortality/aging

neonatal lethality, complete penetrance ( J:60751 )

• homozygotes develop to term but die shortly after birth from a central respiratory failure

• homozygotes die from hypoventilation within 24 hrs of birth, even when respiration is transiently initiated by mechanical stimulation

homeostasis/metabolism

cyanosis ( J:60751 )

• most newborn pups exhibit severe cyanosis

respiratory system

abnormal breathing pattern ( J:60751 )

• C4 vetral root recordings in medulla-spinal cord preparations from newborn homozygotes reveal a rapid respiratory rate with shorter inspiratory duration and intermittent respiratory arrest of ~7.4 sec in duration relative to wild-type controls

tachypnea ( J:60751 )

• during non-apnea periods, homozygotes display an increased respiratory rate relative to wild-type mice

apnea ( J:60751 )

• most newborn homozygotes display immediate apnea

• electromyographic activity of intercostal muscles indicates a high incidence of apnea episodes of up to 20 sec in duration

• mutant pups exhibit an average of ~13 apnea episodes of more than or equal to 5 sec during 10 min of observation relative to only 1 episode in wild-type mice

• the average duration of an apnea episode is nearly doubled in mutant mice relative to wild-type mice

respiratory distress ( J:60751 )

respiratory failure ( J:60751 )

nervous system

nervous system phenotype ( J:60751 )

N • homozygotes show no major histopathologic abnormalities in cranial sensory neurons and brain nuclei

N • no significant neuron loss or gliosis is observed

abnormal dorsal interneuron 2 morphology ( J:76655 )

• homozygotes display abnormal D2 interneuron development, as suggested by loss of Isl1 expression (a marker for D2 interneurons) in the dorsal spinal cord at E11.5

abnormal dorsal interneuron 4 morphology ( J:76655 )

• homozygotes display abnormal D4 interneuron development in the caudal spinal cord, as indicated by expression loss of both Lmx1b and Phox2a in ventrally migrating D4 interneurons at E11.5; in contrast, the most dorsal Lmx1b expression is unaffected

abnormal nervous system physiology ( J:60751 )

• newborn homozygotes display a functional disorder in the central pattern generator of respiration in the ventral medulla

• a coordinate pattern is observed in which failure of inspiratory neuron firing correlates with the respiratory arrest measured as C4 ventral root activity

behavior/neurological

absent gastric milk in neonates ( J:60751 )

• newborn homozygotes always lack gastric milk

immune system

immune system phenotype ( J:60751 )

N • newborn homozygotes display fully developed spleens

digestive/alimentary system

digestive/alimentary phenotype ( J:60751 )

N • newborn homozygotes do not display colonic abnormalities

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
congenital central hypoventilation syndrome		DOID:0060731	OMIM:209880	J:60751

Genotype
MGI:3773047

cx3

• Allelic Composition: Lbx1^tm1Gld/Lbx1^tm1Gld; Tlx3^tm1Sjk/Tlx3^tm1Sjk
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

nervous system

nervous system phenotype ( J:102513 )

N • at hindlimb level, reduction in glutaminergic neurons observed in Lbx1 mutants is reversed

abnormal GABAergic neuron morphology ( J:102513 )

• at age E12.5, neurons expressing GABAergic markers are reduced in dorsal spinal cord; similar to phenotype observed in Lbx1-single mutants

Genotype
MGI:3807393

cx4

• Allelic Composition: Tlx1^tm1Sjk/Tlx1^tm1Sjk; Tlx3^tm1Sjk/Tlx3^tm1Sjk
• Genetic Background: involves: 129S2/SvPas * 129X1/SvJ

nervous system

abnormal sensory neuron morphology ( J:76655 )

• double homozygotes exhibit improper development of most relay somatic sensory neurons, including the spinal-trigeminal nucleus, the dorsal horn of the spinal cord, and a portion of the principle trigeminal nucleus, as indicated by the loss or reduction of expression of specific molecular markers, and by the failure of ingrowth of trkA⁺ afferents to the trigeminal nucleus and the dorsal horn of the spinal cord

abnormal sensory neuron innervation pattern ( J:76655 )

• at E14.5, trkA⁺ nociceptive/thermoceptive sensory afferents from double homozygous mutant mice are able to reach the dorsal entry zone but fail to enter the dorsal horn, unlike wild-type trkA⁺ afferents which start forming collateral branches into the spinal cord

• at E18.5, the ingrowth of trkA⁺ afferents in the double mutant spinal cord is much shallower than the projections noted in wild-type embryos; a similar defect is observed in the ingrowth of cranial trkA⁺ afferents to the spinal-trigeminal nucleus

• in contrast, projection of a subset of trkA⁺ afferents to the deep laminae of the spinal cord appears normal

• also, neuronal migration of dorsal horn neurons appears unaffected, as suggested by similar BrdU pulse-chase labeling patterns in wild-type and double mutant embryos

abnormal spinal cord morphology ( J:134327 )

• at E14.5, number of somatostatin expressing neurons in dorsal spinal cord is increased 5-fold compared to wild-type embryos; most of the increase in neurons is confined to intermediate and deep dorsal laminas

abnormal dorsal interneuron morphology ( J:76655 )

• double homozygotes exhibit improper formation of two classes of dorsal interneurons, D2 and D4, as indicated by loss of specific marker (Isl1 and Lmx1b) expression

• double homozygotes display defective medullary D4 interneuron formation, as indicated by expression loss of both Lmx1b and Phox2a in the lateral area; not observed in single Tlx3^tm1Sjk homozygotes

• however, no enhanced cell death is detected in E11.5-E14.5 double mutant embryos, as shown by TUNEL analysis

abnormal dorsal interneuron 2 morphology ( J:76655 )

abnormal dorsal interneuron 4 morphology ( J:76655 )

abnormal spinal cord dorsal horn morphology ( J:134327 )

• number of somatostatin expressing neurons is reduced 5-fold in dorsal spinal cord at E18.75 due to absence of somatostatin in dorsal horn