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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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Novel observations in Porcn+/del FDH mouse model.In contrast to control Porcn+/+ animals, adult Porcn+/del females exhibit lesions suggestive of ciliary defects (A-H). Mutants exhibited otitis media (n=4/5, B), rhinitis (n=2/5, D), and bronchopneumonia (n=3/5, F). Mild hydrocephalus was observed in 2/5 Porcn+/del females (H). Arrowhead indicates enlarged third ventricle (H).Bronchopneumonia was characterized by large numbers of inflammatory cells and plant material/bedding in the bronchioles (arrowhead, J), and was accompanied by mild right ventricular hypertrophy (arrowhead, L). Mutant bronchiole epithelia had increased numbers of goblet cells (N, pink cells, arrowhead) in areas of inflammation as indicated by the presence of intraluminal inflammatory cells (N, arrow). Tracheal epithelia of mutants were mildly disorganized (P) and lacked cilia in segments of up to 200 μm long compared to controls (O, arrowhead).Consistent with chronic active inflammation, hematology profiles showed significant increases in white blood cells (WBC, Q), lymphocytes (R), monocytes (S), and neutrophils (T). Red blood cell (RBC) counts (U) and hemoglobin concentration (V) were also elevated. Blood cell counts were analyzed by unpaired student’s t-test.Figures A-L: Hematoxylin & Eosin (H&E) stained sections. Figures M-P: Periodic Acid-Schiff (PAS) stained sections.
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pone-0079139-g007: Novel observations in Porcn+/del FDH mouse model.In contrast to control Porcn+/+ animals, adult Porcn+/del females exhibit lesions suggestive of ciliary defects (A-H). Mutants exhibited otitis media (n=4/5, B), rhinitis (n=2/5, D), and bronchopneumonia (n=3/5, F). Mild hydrocephalus was observed in 2/5 Porcn+/del females (H). Arrowhead indicates enlarged third ventricle (H).Bronchopneumonia was characterized by large numbers of inflammatory cells and plant material/bedding in the bronchioles (arrowhead, J), and was accompanied by mild right ventricular hypertrophy (arrowhead, L). Mutant bronchiole epithelia had increased numbers of goblet cells (N, pink cells, arrowhead) in areas of inflammation as indicated by the presence of intraluminal inflammatory cells (N, arrow). Tracheal epithelia of mutants were mildly disorganized (P) and lacked cilia in segments of up to 200 μm long compared to controls (O, arrowhead).Consistent with chronic active inflammation, hematology profiles showed significant increases in white blood cells (WBC, Q), lymphocytes (R), monocytes (S), and neutrophils (T). Red blood cell (RBC) counts (U) and hemoglobin concentration (V) were also elevated. Blood cell counts were analyzed by unpaired student’s t-test.Figures A-L: Hematoxylin & Eosin (H&E) stained sections. Figures M-P: Periodic Acid-Schiff (PAS) stained sections.

Mentions: In contrast to control animals, adult Porcn+/del females exhibited combinations of mucociliary clearance defects: otitis media (4/5, Figure 7A, B), rhinitis (2/5, Figure 7C, D), and bronchopneumonia with bronchiectasis (3/5, Figure 7E, F). Additionally, mild bilateral hydrocephalus of the third ventricle was also seen in some females (2/5, Figure 7G, H). In FDH model mice the pneumonia was characterized by pyogranulomatous inflammation centered on foreign material (hair, food, and bedding) and colonies of coccoid bacteria within the bronchioles, consistent with aspiration pneumonia (Figure 7I, J). Aspiration pneumonia is rare in mice and its presence only in mutants argues against environmental or iatrogenic causes. Consistent with our findings, recurrent pneumonia has been reported in some FDH patients in association with gastroesophageal reflux and nasal regurgitation during feeding [27,29]. It is not known if there are lung defects that are associated with this symptom in humans. Mild right ventricular hypertrophy of the heart was observed in some mice (Figure 7K, L), which is likely secondary to pulmonary hypertension associated with pneumonia. Consistent with the observed chronic, active pulmonary inflammation, we detected significant increases in white blood cell counts, lymphocytes, monocytes and neutrophils (Figure 7Q-T). We furthermore detected an increase in red blood cell counts (Figure 7U) and significant increases in total hemoglobin concentration (Figure 7V). Whether these increases are due to dehydration or an adaptive response to poor lung function is not clear.


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

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

Novel observations in Porcn+/del FDH mouse model.In contrast to control Porcn+/+ animals, adult Porcn+/del females exhibit lesions suggestive of ciliary defects (A-H). Mutants exhibited otitis media (n=4/5, B), rhinitis (n=2/5, D), and bronchopneumonia (n=3/5, F). Mild hydrocephalus was observed in 2/5 Porcn+/del females (H). Arrowhead indicates enlarged third ventricle (H).Bronchopneumonia was characterized by large numbers of inflammatory cells and plant material/bedding in the bronchioles (arrowhead, J), and was accompanied by mild right ventricular hypertrophy (arrowhead, L). Mutant bronchiole epithelia had increased numbers of goblet cells (N, pink cells, arrowhead) in areas of inflammation as indicated by the presence of intraluminal inflammatory cells (N, arrow). Tracheal epithelia of mutants were mildly disorganized (P) and lacked cilia in segments of up to 200 μm long compared to controls (O, arrowhead).Consistent with chronic active inflammation, hematology profiles showed significant increases in white blood cells (WBC, Q), lymphocytes (R), monocytes (S), and neutrophils (T). Red blood cell (RBC) counts (U) and hemoglobin concentration (V) were also elevated. Blood cell counts were analyzed by unpaired student’s t-test.Figures A-L: Hematoxylin & Eosin (H&E) stained sections. Figures M-P: Periodic Acid-Schiff (PAS) stained sections.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3815152&req=5

pone-0079139-g007: Novel observations in Porcn+/del FDH mouse model.In contrast to control Porcn+/+ animals, adult Porcn+/del females exhibit lesions suggestive of ciliary defects (A-H). Mutants exhibited otitis media (n=4/5, B), rhinitis (n=2/5, D), and bronchopneumonia (n=3/5, F). Mild hydrocephalus was observed in 2/5 Porcn+/del females (H). Arrowhead indicates enlarged third ventricle (H).Bronchopneumonia was characterized by large numbers of inflammatory cells and plant material/bedding in the bronchioles (arrowhead, J), and was accompanied by mild right ventricular hypertrophy (arrowhead, L). Mutant bronchiole epithelia had increased numbers of goblet cells (N, pink cells, arrowhead) in areas of inflammation as indicated by the presence of intraluminal inflammatory cells (N, arrow). Tracheal epithelia of mutants were mildly disorganized (P) and lacked cilia in segments of up to 200 μm long compared to controls (O, arrowhead).Consistent with chronic active inflammation, hematology profiles showed significant increases in white blood cells (WBC, Q), lymphocytes (R), monocytes (S), and neutrophils (T). Red blood cell (RBC) counts (U) and hemoglobin concentration (V) were also elevated. Blood cell counts were analyzed by unpaired student’s t-test.Figures A-L: Hematoxylin & Eosin (H&E) stained sections. Figures M-P: Periodic Acid-Schiff (PAS) stained sections.
Mentions: In contrast to control animals, adult Porcn+/del females exhibited combinations of mucociliary clearance defects: otitis media (4/5, Figure 7A, B), rhinitis (2/5, Figure 7C, D), and bronchopneumonia with bronchiectasis (3/5, Figure 7E, F). Additionally, mild bilateral hydrocephalus of the third ventricle was also seen in some females (2/5, Figure 7G, H). In FDH model mice the pneumonia was characterized by pyogranulomatous inflammation centered on foreign material (hair, food, and bedding) and colonies of coccoid bacteria within the bronchioles, consistent with aspiration pneumonia (Figure 7I, J). Aspiration pneumonia is rare in mice and its presence only in mutants argues against environmental or iatrogenic causes. Consistent with our findings, recurrent pneumonia has been reported in some FDH patients in association with gastroesophageal reflux and nasal regurgitation during feeding [27,29]. It is not known if there are lung defects that are associated with this symptom in humans. Mild right ventricular hypertrophy of the heart was observed in some mice (Figure 7K, L), which is likely secondary to pulmonary hypertension associated with pneumonia. Consistent with the observed chronic, active pulmonary inflammation, we detected significant increases in white blood cell counts, lymphocytes, monocytes and neutrophils (Figure 7Q-T). We furthermore detected an increase in red blood cell counts (Figure 7U) and significant increases in total hemoglobin concentration (Figure 7V). Whether these increases are due to dehydration or an adaptive response to poor lung function is not clear.

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