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Zygotic Porcn paternal allele deletion in mice to model human focal dermal hypoplasia.

Biechele S, Adissu HA, Cox BJ, Rossant J - PLoS ONE (2013)

Bottom Line: This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns.We show that heterozygous female fetuses display variable defects that do not significantly affect survival in the uterus, but lead to perinatal lethality in more than 95% of females.Although not frequently reported in humans, we also observed bronchopneumonia, rhinitis, and otitis media in these animals, suggesting a potential link between Porcn function and the normal development of ciliated cells in these tissues.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
In mouse and humans, the X-chromosomal Porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands, thus representing a bottleneck in the secretion of Wnt ligands. In humans, mutations in PORCN cause the X-linked dominant syndrome Focal Dermal Hypoplasia (FDH, OMIM#305600). This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns. To improve the understanding of human FDH, we have established a mouse model by generation of Porcn heterozygous animals carrying a zygotic deletion of the paternal allele. We show that heterozygous female fetuses display variable defects that do not significantly affect survival in the uterus, but lead to perinatal lethality in more than 95% of females. Rare survivors develop to adulthood and display variable skeletal and skin defects, representing an adult zygotic mouse model for human FDH. Although not frequently reported in humans, we also observed bronchopneumonia, rhinitis, and otitis media in these animals, suggesting a potential link between Porcn function and the normal development of ciliated cells in these tissues.

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Analysis of survival of Porcn+/del fetuses and neonates.At fetal stages (E11.5 to E18.5) Porcn+/del females were observed at the expected Mendelian frequency (50%). At birth (P0) only 7.4% of the live neonates observed were female. Lethality in the first week of life further reduced this frequency to 3.5% (10 out of 277 expected) at postnatal day 7 (P7).
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pone-0079139-g002: Analysis of survival of Porcn+/del fetuses and neonates.At fetal stages (E11.5 to E18.5) Porcn+/del females were observed at the expected Mendelian frequency (50%). At birth (P0) only 7.4% of the live neonates observed were female. Lethality in the first week of life further reduced this frequency to 3.5% (10 out of 277 expected) at postnatal day 7 (P7).

Mentions: Despite the functional rescue of placental phenotypes, we noted that heterozygous females were underrepresented in newborn litters and a large percentage of these mice were lost due to perinatal mortality (Figure 2). However, by breeding larger numbers of mice, rare survivors were identified. Despite observations of occasional fetal lethality, we were able to observe Porcn+/del female fetuses up to E18.5 with no significant deviations from the expected frequency (50%, Figure 2), suggesting that the majority of malformations observed does not impinge on embryonic survival. Assessment of litters at birth (P0), however, revealed that most Porcn+/del females die perinatally and are cannibalized by the mothers, as only 7.4% of live pups were female (n=22/299,Figure 2). By postnatal day 7 (P7), only 3.5% female pups were alive (n=10/287), indicating a high rate of perinatal lethality (Figure 2). No unusual lethality was observed past P7.


Zygotic Porcn paternal allele deletion in mice to model human focal dermal hypoplasia.

Biechele S, Adissu HA, Cox BJ, Rossant J - PLoS ONE (2013)

Analysis of survival of Porcn+/del fetuses and neonates.At fetal stages (E11.5 to E18.5) Porcn+/del females were observed at the expected Mendelian frequency (50%). At birth (P0) only 7.4% of the live neonates observed were female. Lethality in the first week of life further reduced this frequency to 3.5% (10 out of 277 expected) at postnatal day 7 (P7).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815152&req=5

pone-0079139-g002: Analysis of survival of Porcn+/del fetuses and neonates.At fetal stages (E11.5 to E18.5) Porcn+/del females were observed at the expected Mendelian frequency (50%). At birth (P0) only 7.4% of the live neonates observed were female. Lethality in the first week of life further reduced this frequency to 3.5% (10 out of 277 expected) at postnatal day 7 (P7).
Mentions: Despite the functional rescue of placental phenotypes, we noted that heterozygous females were underrepresented in newborn litters and a large percentage of these mice were lost due to perinatal mortality (Figure 2). However, by breeding larger numbers of mice, rare survivors were identified. Despite observations of occasional fetal lethality, we were able to observe Porcn+/del female fetuses up to E18.5 with no significant deviations from the expected frequency (50%, Figure 2), suggesting that the majority of malformations observed does not impinge on embryonic survival. Assessment of litters at birth (P0), however, revealed that most Porcn+/del females die perinatally and are cannibalized by the mothers, as only 7.4% of live pups were female (n=22/299,Figure 2). By postnatal day 7 (P7), only 3.5% female pups were alive (n=10/287), indicating a high rate of perinatal lethality (Figure 2). No unusual lethality was observed past P7.

Bottom Line: This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns.We show that heterozygous female fetuses display variable defects that do not significantly affect survival in the uterus, but lead to perinatal lethality in more than 95% of females.Although not frequently reported in humans, we also observed bronchopneumonia, rhinitis, and otitis media in these animals, suggesting a potential link between Porcn function and the normal development of ciliated cells in these tissues.

View Article: PubMed Central - PubMed

Affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
In mouse and humans, the X-chromosomal Porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands, thus representing a bottleneck in the secretion of Wnt ligands. In humans, mutations in PORCN cause the X-linked dominant syndrome Focal Dermal Hypoplasia (FDH, OMIM#305600). This disorder is characterized by ecto-mesodermal dysplasias and shows a highly variable phenotype, potentially due to individual X chromosome inactivation patterns. To improve the understanding of human FDH, we have established a mouse model by generation of Porcn heterozygous animals carrying a zygotic deletion of the paternal allele. We show that heterozygous female fetuses display variable defects that do not significantly affect survival in the uterus, but lead to perinatal lethality in more than 95% of females. Rare survivors develop to adulthood and display variable skeletal and skin defects, representing an adult zygotic mouse model for human FDH. Although not frequently reported in humans, we also observed bronchopneumonia, rhinitis, and otitis media in these animals, suggesting a potential link between Porcn function and the normal development of ciliated cells in these tissues.

Show MeSH
Related in: MedlinePlus