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Mice lacking DYRK2 exhibit congenital malformations with lung hypoplasia and altered Foxf1 expression gradient
Satomi Yogosawa1, Makiko Ohkido2, Takuro Horii3
1Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan.
Abstract:
Congenital malformations cause life-threatening diseases in pediatrics, yet the molecular mechanism of organogenesis is poorly understood. Here we show that Dyrk2-deficient mice display congenital malformations in multiple organs. Transcriptome analysis reveals molecular pathology of Dyrk2-deficient mice, particularly with respect to Foxf1 reduction. Mutant pups exhibit sudden death soon after birth due to respiratory failure. Detailed analyses of primordial lungs at the early developmental stage demonstrate that Dyrk2 deficiency leads to altered airway branching and insufficient alveolar development. Furthermore, the Foxf1 expression gradient in mutant lung mesenchyme is disrupted, reducing Foxf1 target genes, which are necessary for proper airway and alveolar development. In ex vivo lung culture system, we rescue the expression of Foxf1 and its target genes in Dyrk2-deficient lung by restoring Shh signaling activity. Taken together, we demonstrate that Dyrk2 is essential for embryogenesis and its disruption results in congenital malformation.
Insights
Dyrk2 deficiency causes congenital malformations and respiratory failure in newborn mice by disrupting lung development and Foxf1 expression. Restoring Shh signaling partially rescues these defects.
Area of Science:
- Developmental Biology
- Genetics
- Pediatric Pathology
Background:
- Congenital malformations pose significant risks in pediatrics.
- The molecular underpinnings of organogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the role of Dyrk2 in organogenesis and its potential link to congenital malformations.
- To elucidate the molecular mechanisms underlying Dyrk2-deficiency-induced developmental defects, focusing on lung development.
Main Methods:
- Generation and analysis of Dyrk2-deficient mice.
- Transcriptome analysis to identify molecular pathologies.
- Detailed histological and developmental analyses of primordial lungs.
- Ex vivo lung culture to test rescue strategies.
Main Results:
- Dyrk2-deficient mice exhibit multiple congenital malformations and post-natal lethality due to respiratory failure.
- Reduced Foxf1 expression and disrupted signaling pathways were observed in Dyrk2-deficient lungs.
- Impaired airway branching and alveolar development were evident in mutant lungs.
- Restoration of Shh signaling in ex vivo cultures partially rescued Foxf1 expression and target genes.
Conclusions:
- Dyrk2 is crucial for mammalian embryogenesis and proper organ development.
- Disruption of Dyrk2 leads to congenital malformations, particularly affecting lung morphogenesis via Foxf1 regulation.
- Shh signaling pathway modulation presents a potential therapeutic avenue for Dyrk2-related developmental disorders.
