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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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Histological analysis of Porcn+/del females at E18.5.At E18.5, in contrast to control Porcn+/Y littermates (A), several Porcn+/del females exhibited body wall closure defects (B, n=5/9), diaphragmatic hernias (C, n=5/9), and signs of spina bifida (D, open arrowhead, n=1/9). Arrows indicate the diaphragm. Arrowheads indicate the anterior body wall. Approximately 45% (n=4/9) heterozygous females displayed signs of severe kidney disease, such as hydronephrosis (F), which was not observed in control littermates (E). The skin of the majority of Porcn+/del fetuses (H, n=6/9) displayed signs of focal dermal hypoplasia as evidenced by reduction/absence of adnexa (arrowheads) (G,H).
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pone-0079139-g004: Histological analysis of Porcn+/del females at E18.5.At E18.5, in contrast to control Porcn+/Y littermates (A), several Porcn+/del females exhibited body wall closure defects (B, n=5/9), diaphragmatic hernias (C, n=5/9), and signs of spina bifida (D, open arrowhead, n=1/9). Arrows indicate the diaphragm. Arrowheads indicate the anterior body wall. Approximately 45% (n=4/9) heterozygous females displayed signs of severe kidney disease, such as hydronephrosis (F), which was not observed in control littermates (E). The skin of the majority of Porcn+/del fetuses (H, n=6/9) displayed signs of focal dermal hypoplasia as evidenced by reduction/absence of adnexa (arrowheads) (G,H).

Mentions: As noted in human FDH as well as previous observations in mice [15], we found a wide spectrum of defects during fetal development of Porcn+/del females. Typical defects included posterior truncations (Figure 3A, B) reminiscent of Cdx1::Cre deletions of the downstream Wnt signaling component Ctnnb1 [25], body wall closure defects and defects in tail development (Figure 3C, D), as well as craniofacial defects (data not shown). We additionally observed variable limb development defects including syndactyly, polydactyly, oligodactyly with features of ectrodactyly, and more severe malformations such as absence of feet and digits (peromelia). In order to investigate the cause of perinatal lethality in more detail, we assessed midsagittal and parasagittal sections of fetuses just prior to birth (E18.5). While some Porcndel/+ fetuses (n=2/9) and Porcn+/Y littermates (n=2/2) showed no obvious abnormalities (Figure 4A), the majority of fetuses (n=7/9) exhibited multiple defects potentially responsible for the observed perinatal lethality. These individually variable defects could be grouped into four categories; thoracic body wall defects (n=5/9, Figure 4B), diaphragmatic hernias with abdominal organs protruding into the thoracic cavity (n=5/9, Figure 4C), kidney defects such as hydronephrosis and hydroureter (n=4/9, Figure 4E, F), and midline closure defects (Figure 3 D). We furthermore observed a high frequency of fetuses with focal dermal hypoplasia (n=6/9, Figure 4G, H), which can be excluded as cause of lethality, but is the name-giving feature of the human disease FDH. Thoracic body wall defects and diaphragmatic hernias are likely to impair lung function and compromise postnatal survival. Moreover, severe kidney defects can also cause lethality within the first days of life. Together with midline closure defects that expose organs to the exterior, these defects explain the perinatal lethality observed in Porcn+/del females.


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

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

Histological analysis of Porcn+/del females at E18.5.At E18.5, in contrast to control Porcn+/Y littermates (A), several Porcn+/del females exhibited body wall closure defects (B, n=5/9), diaphragmatic hernias (C, n=5/9), and signs of spina bifida (D, open arrowhead, n=1/9). Arrows indicate the diaphragm. Arrowheads indicate the anterior body wall. Approximately 45% (n=4/9) heterozygous females displayed signs of severe kidney disease, such as hydronephrosis (F), which was not observed in control littermates (E). The skin of the majority of Porcn+/del fetuses (H, n=6/9) displayed signs of focal dermal hypoplasia as evidenced by reduction/absence of adnexa (arrowheads) (G,H).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3815152&req=5

pone-0079139-g004: Histological analysis of Porcn+/del females at E18.5.At E18.5, in contrast to control Porcn+/Y littermates (A), several Porcn+/del females exhibited body wall closure defects (B, n=5/9), diaphragmatic hernias (C, n=5/9), and signs of spina bifida (D, open arrowhead, n=1/9). Arrows indicate the diaphragm. Arrowheads indicate the anterior body wall. Approximately 45% (n=4/9) heterozygous females displayed signs of severe kidney disease, such as hydronephrosis (F), which was not observed in control littermates (E). The skin of the majority of Porcn+/del fetuses (H, n=6/9) displayed signs of focal dermal hypoplasia as evidenced by reduction/absence of adnexa (arrowheads) (G,H).
Mentions: As noted in human FDH as well as previous observations in mice [15], we found a wide spectrum of defects during fetal development of Porcn+/del females. Typical defects included posterior truncations (Figure 3A, B) reminiscent of Cdx1::Cre deletions of the downstream Wnt signaling component Ctnnb1 [25], body wall closure defects and defects in tail development (Figure 3C, D), as well as craniofacial defects (data not shown). We additionally observed variable limb development defects including syndactyly, polydactyly, oligodactyly with features of ectrodactyly, and more severe malformations such as absence of feet and digits (peromelia). In order to investigate the cause of perinatal lethality in more detail, we assessed midsagittal and parasagittal sections of fetuses just prior to birth (E18.5). While some Porcndel/+ fetuses (n=2/9) and Porcn+/Y littermates (n=2/2) showed no obvious abnormalities (Figure 4A), the majority of fetuses (n=7/9) exhibited multiple defects potentially responsible for the observed perinatal lethality. These individually variable defects could be grouped into four categories; thoracic body wall defects (n=5/9, Figure 4B), diaphragmatic hernias with abdominal organs protruding into the thoracic cavity (n=5/9, Figure 4C), kidney defects such as hydronephrosis and hydroureter (n=4/9, Figure 4E, F), and midline closure defects (Figure 3 D). We furthermore observed a high frequency of fetuses with focal dermal hypoplasia (n=6/9, Figure 4G, H), which can be excluded as cause of lethality, but is the name-giving feature of the human disease FDH. Thoracic body wall defects and diaphragmatic hernias are likely to impair lung function and compromise postnatal survival. Moreover, severe kidney defects can also cause lethality within the first days of life. Together with midline closure defects that expose organs to the exterior, these defects explain the perinatal lethality observed in Porcn+/del females.

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