Tgfbeta2 -/- Tgfbeta3 -/- double knockout mice display severe midline fusion defects and early embryonic lethality
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Nicole Dünker1, Kerstin Krieglstein
1Department of Neuroanatomy, Georg August University Göttingen, 37075 Göttingen, German. nduenke@gwdg.de
Abstract:
Given all known biological activities, it is anticipated that transforming growth factors beta (TGF-betas) play important roles in many different developmental processes. As all three TGF-beta isoforms display overlapping expression patterns, deletion of one TGF-beta isoform might be compensated for by another. In the present study, targeted disruption of both Tgfbeta2 and Tgfbeta3 genes was undertaken to circumvent this problem and determine the essential roles of TGF-beta2 and TGF-beta3 in vivo. Tgfbeta2(-/-) Tgfbeta3(-/-) double knockout mice and their three-allelic Tgfbeta2(-/-) Tgfbeta3(+/-) littermates display a lack of distal parts of the rib, a lack of sternal primordia, and failure in ventral body wall closure, leading to an extrathoracic position of the heart and extrusion of the liver. In addition, abnormalities in connective tissue composition and an early embryonic lethality [around embryonic day (E) 15.5] are seen. In contrast, Tgfbeta2 (+/-) Tgfbeta3 (-/-) littermates show normal rib and sternum development, normal anterior body wall fusion, and are still alive on E18.5. TGF-beta2 is already known to play a role in skeletal and craniofacial development. The results presented here show that beyond this: (a). TGF-betas obviously play a fundamental role in midline fusion and (b). the Tgfbeta2 gene seems to play a more important role in mediating developmental processes than the Tgfbeta3 gene, since Tgfbeta2 (+/-) Tgfbeta3 (-/-) mutants - in contrast to their Tgfbeta2(-/-) Tgfbeta3 (+)(/-) littermates - do not display severe malformations.
Insights
Targeted gene disruption in mice reveals transforming growth factors beta (TGF-betas) are crucial for ventral body wall closure and embryonic development. Tgfbeta2 plays a more significant role than Tgfbeta3 in these processes.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Transforming growth factors beta (TGF-betas) are known to influence various developmental processes.
- Overlapping expression patterns of TGF-beta isoforms suggest potential functional redundancy.
- Understanding the specific roles of individual TGF-beta isoforms in vivo is essential.
Purpose of the Study:
- To determine the essential roles of TGF-beta2 and TGF-beta3 in vivo by creating double knockout mice.
- To investigate the necessity of TGF-beta2 and TGF-beta3 in embryonic development, specifically in midline fusion and organ positioning.
Main Methods:
- Generation of Tgfbeta2(-/-) Tgfbeta3(-/-) double knockout mice and Tgfbeta2(+/-) Tgfbeta3(-/-) compound heterozygous littermates.
- Phenotypic analysis of knockout mice, focusing on skeletal development, body wall closure, and organ positioning.
- Assessment of embryonic lethality and developmental timing.
Main Results:
- Tgfbeta2(-/-) Tgfbeta3(-/-) mice exhibit severe malformations including lack of ribs and sternum, ventral body wall defects, and embryonic lethality around E15.5.
- These double knockouts show an extrathoracic heart and extruded liver due to failed ventral body wall closure.
- Tgfbeta2(+/-) Tgfbeta3(-/-) mice display normal development, indicating Tgfbeta2 plays a more critical role than Tgfbeta3 in these specific developmental processes.
Conclusions:
- TGF-betas are fundamentally important for midline fusion during embryonic development.
- The Tgfbeta2 gene is more critical than the Tgfbeta3 gene in mediating key developmental processes, including ventral body wall closure.
- Loss of Tgfbeta2 function leads to severe developmental defects, while partial loss combined with Tgfbeta3 null does not.
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