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Cleft Palate, Moderate Lung Developmental Retardation and Early Postnatal Lethality in Mice Deficient in the Kir7.1 Inwardly Rectifying K+ Channel.

Villanueva S, Burgos J, López-Cayuqueo KI, Lai KM, Valenzuela DM, Cid LP, Sepúlveda FV - PLoS ONE (2015)

Bottom Line: Kir7.1 is present in epithelial tissues where it colocalizes with the Na+/K+-pump probably serving to recycle K+ taken up by the pump.Kir7.1 is expressed in the epithelium covering the palatal processes at the time at which palate sealing takes place and our results suggest it might play an essential role in late palatogenesis.Our work also reveals a second unexpected role in the development and the physiology of the respiratory system, where Kir7.1 is expressed in epithelial cells all along the respiratory tree.

View Article: PubMed Central - PubMed

Affiliation: Centro de Estudios Científicos (CECs), Valdivia, Chile.

ABSTRACT
Kir7.1 is an inwardly rectifying K+ channel of the Kir superfamily encoded by the kcnj13 gene. Kir7.1 is present in epithelial tissues where it colocalizes with the Na+/K+-pump probably serving to recycle K+ taken up by the pump. Human mutations affecting Kir7.1 are associated with retinal degeneration diseases. We generated a mouse lacking Kir7.1 by ablation of the Kcnj13 gene. Homozygous mutant mice die hours after birth and show cleft palate and moderate retardation in lung development. Kir7.1 is expressed in the epithelium covering the palatal processes at the time at which palate sealing takes place and our results suggest it might play an essential role in late palatogenesis. Our work also reveals a second unexpected role in the development and the physiology of the respiratory system, where Kir7.1 is expressed in epithelial cells all along the respiratory tree.

No MeSH data available.


Related in: MedlinePlus

Morphology and body weights of Kcnj13  mutant mice.a. Analysis of Kir7.1 expression in WT, heterozygous and  mutant mice; cyclophilin A (Cyc1) is used as constitutively expressed control gene. b. Gross morphology of WT, and heterozygous and homozygous Kcnj13  mutant newborn pups. c. Body weight vs. embryonic stage for WT (circles), Kcnj13+/- (triangles), and Kcnj13-/- (squares) embryos. Results are expressed as mean ± S.E.M. of the following numbers of embryos: 12.5 dpc: WT 3, Kcnj13+/- 9, Kcnj13-/- 4; 13.5 dpc: WT 9, Kcnj13+/- 14, Kcnj13-/- 2; n 14.5 dpc: WT 3, Kcnj13+/- 11, Kcnj13-/- 6; 15.5 dpc: WT 7, Kcnj13+/- 20, Kcnj13-/- 14; 16.5 dpc: WT 7, Kcnj13+/- 5, Kcnj13-/- 4; 17.5 dpc:WT 5, Kcnj13+/- 12, Kcnj13-/- 6; 18.5 dpc: WT 4, Kcnj13+/- 5, Kcnj13-/- 6; P0: WT 7, Kcnj13+/- 15, Kcnj13-/- 10. * p< 0.001; ** p <0.05 for the differences between Kcnj13-/- and Kcnj13+/+ data (ANOVA).
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pone.0139284.g001: Morphology and body weights of Kcnj13 mutant mice.a. Analysis of Kir7.1 expression in WT, heterozygous and mutant mice; cyclophilin A (Cyc1) is used as constitutively expressed control gene. b. Gross morphology of WT, and heterozygous and homozygous Kcnj13 mutant newborn pups. c. Body weight vs. embryonic stage for WT (circles), Kcnj13+/- (triangles), and Kcnj13-/- (squares) embryos. Results are expressed as mean ± S.E.M. of the following numbers of embryos: 12.5 dpc: WT 3, Kcnj13+/- 9, Kcnj13-/- 4; 13.5 dpc: WT 9, Kcnj13+/- 14, Kcnj13-/- 2; n 14.5 dpc: WT 3, Kcnj13+/- 11, Kcnj13-/- 6; 15.5 dpc: WT 7, Kcnj13+/- 20, Kcnj13-/- 14; 16.5 dpc: WT 7, Kcnj13+/- 5, Kcnj13-/- 4; 17.5 dpc:WT 5, Kcnj13+/- 12, Kcnj13-/- 6; 18.5 dpc: WT 4, Kcnj13+/- 5, Kcnj13-/- 6; P0: WT 7, Kcnj13+/- 15, Kcnj13-/- 10. * p< 0.001; ** p <0.05 for the differences between Kcnj13-/- and Kcnj13+/+ data (ANOVA).

Mentions: In order to study the physiological role of Kir7.1 inwardly rectifying K+ channel we generated Kir7.1 deficient mice by ablation of its codifying Kcnj13 gene by the Velocigene method [19]. Effective gene deletion was evaluated by studying the gene expression in lung and brain tissue of P0 pups by RT-PCR (Fig 1a). The transcript was absent from Kcnj13-/- mutant mice as expected. Heterozygous Kcnj13+/- mice were indistinguishable from their wild type Kcnj13+/+ litter mates in growth and development. Homozygous mutant mice however failed to suckle, were often cannibalised by their mothers and did not survive beyond P0. Because of extensive cannibalism we were initially under the impression most of the mice died in utero, but cesarean delivery and genotyping revealed a Mendelian distribution of the three genotypes in embryos generated after crossing heterozygous mice (Table 1). Also, careful surveillance and separation of newborn mice showed that delivery produced litters with Mendelian distribution of genotypes (Table 1). Newborn mutant mice were slightly smaller than their heterozygous of wild-type littermates (Fig 1b). This difference was significant and was also present in the embryos from stage E15.5 onwards (Fig 1c).


Cleft Palate, Moderate Lung Developmental Retardation and Early Postnatal Lethality in Mice Deficient in the Kir7.1 Inwardly Rectifying K+ Channel.

Villanueva S, Burgos J, López-Cayuqueo KI, Lai KM, Valenzuela DM, Cid LP, Sepúlveda FV - PLoS ONE (2015)

Morphology and body weights of Kcnj13  mutant mice.a. Analysis of Kir7.1 expression in WT, heterozygous and  mutant mice; cyclophilin A (Cyc1) is used as constitutively expressed control gene. b. Gross morphology of WT, and heterozygous and homozygous Kcnj13  mutant newborn pups. c. Body weight vs. embryonic stage for WT (circles), Kcnj13+/- (triangles), and Kcnj13-/- (squares) embryos. Results are expressed as mean ± S.E.M. of the following numbers of embryos: 12.5 dpc: WT 3, Kcnj13+/- 9, Kcnj13-/- 4; 13.5 dpc: WT 9, Kcnj13+/- 14, Kcnj13-/- 2; n 14.5 dpc: WT 3, Kcnj13+/- 11, Kcnj13-/- 6; 15.5 dpc: WT 7, Kcnj13+/- 20, Kcnj13-/- 14; 16.5 dpc: WT 7, Kcnj13+/- 5, Kcnj13-/- 4; 17.5 dpc:WT 5, Kcnj13+/- 12, Kcnj13-/- 6; 18.5 dpc: WT 4, Kcnj13+/- 5, Kcnj13-/- 6; P0: WT 7, Kcnj13+/- 15, Kcnj13-/- 10. * p< 0.001; ** p <0.05 for the differences between Kcnj13-/- and Kcnj13+/+ data (ANOVA).
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Related In: Results  -  Collection

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pone.0139284.g001: Morphology and body weights of Kcnj13 mutant mice.a. Analysis of Kir7.1 expression in WT, heterozygous and mutant mice; cyclophilin A (Cyc1) is used as constitutively expressed control gene. b. Gross morphology of WT, and heterozygous and homozygous Kcnj13 mutant newborn pups. c. Body weight vs. embryonic stage for WT (circles), Kcnj13+/- (triangles), and Kcnj13-/- (squares) embryos. Results are expressed as mean ± S.E.M. of the following numbers of embryos: 12.5 dpc: WT 3, Kcnj13+/- 9, Kcnj13-/- 4; 13.5 dpc: WT 9, Kcnj13+/- 14, Kcnj13-/- 2; n 14.5 dpc: WT 3, Kcnj13+/- 11, Kcnj13-/- 6; 15.5 dpc: WT 7, Kcnj13+/- 20, Kcnj13-/- 14; 16.5 dpc: WT 7, Kcnj13+/- 5, Kcnj13-/- 4; 17.5 dpc:WT 5, Kcnj13+/- 12, Kcnj13-/- 6; 18.5 dpc: WT 4, Kcnj13+/- 5, Kcnj13-/- 6; P0: WT 7, Kcnj13+/- 15, Kcnj13-/- 10. * p< 0.001; ** p <0.05 for the differences between Kcnj13-/- and Kcnj13+/+ data (ANOVA).
Mentions: In order to study the physiological role of Kir7.1 inwardly rectifying K+ channel we generated Kir7.1 deficient mice by ablation of its codifying Kcnj13 gene by the Velocigene method [19]. Effective gene deletion was evaluated by studying the gene expression in lung and brain tissue of P0 pups by RT-PCR (Fig 1a). The transcript was absent from Kcnj13-/- mutant mice as expected. Heterozygous Kcnj13+/- mice were indistinguishable from their wild type Kcnj13+/+ litter mates in growth and development. Homozygous mutant mice however failed to suckle, were often cannibalised by their mothers and did not survive beyond P0. Because of extensive cannibalism we were initially under the impression most of the mice died in utero, but cesarean delivery and genotyping revealed a Mendelian distribution of the three genotypes in embryos generated after crossing heterozygous mice (Table 1). Also, careful surveillance and separation of newborn mice showed that delivery produced litters with Mendelian distribution of genotypes (Table 1). Newborn mutant mice were slightly smaller than their heterozygous of wild-type littermates (Fig 1b). This difference was significant and was also present in the embryos from stage E15.5 onwards (Fig 1c).

Bottom Line: Kir7.1 is present in epithelial tissues where it colocalizes with the Na+/K+-pump probably serving to recycle K+ taken up by the pump.Kir7.1 is expressed in the epithelium covering the palatal processes at the time at which palate sealing takes place and our results suggest it might play an essential role in late palatogenesis.Our work also reveals a second unexpected role in the development and the physiology of the respiratory system, where Kir7.1 is expressed in epithelial cells all along the respiratory tree.

View Article: PubMed Central - PubMed

Affiliation: Centro de Estudios Científicos (CECs), Valdivia, Chile.

ABSTRACT
Kir7.1 is an inwardly rectifying K+ channel of the Kir superfamily encoded by the kcnj13 gene. Kir7.1 is present in epithelial tissues where it colocalizes with the Na+/K+-pump probably serving to recycle K+ taken up by the pump. Human mutations affecting Kir7.1 are associated with retinal degeneration diseases. We generated a mouse lacking Kir7.1 by ablation of the Kcnj13 gene. Homozygous mutant mice die hours after birth and show cleft palate and moderate retardation in lung development. Kir7.1 is expressed in the epithelium covering the palatal processes at the time at which palate sealing takes place and our results suggest it might play an essential role in late palatogenesis. Our work also reveals a second unexpected role in the development and the physiology of the respiratory system, where Kir7.1 is expressed in epithelial cells all along the respiratory tree.

No MeSH data available.


Related in: MedlinePlus