Evolutionäre Neuheiten in der Kopfentwicklung von Amphibien: Die Rolle von FoxN3 und funktionell verwandter Gene in der craniofacialen Entwicklung.
Entwicklungsbiologie
Zusammenfassung der Projektergebnisse
The origin and evolution of novel structures is a classical problem in compararative anatomy and evolutionary embryology (in its modern incarnation as EvoDevo). In this project, we have investigated the developmental basis of evolutionary novelties in the head of amphibian embryos and larvae. Our work includes anatomical descriptions of the normal development of cartilage, muscles and nerves as well as experimental studies. Structures investigated include the jaw joint, the intramandibular joint and the cartilage elements associated with these (e.g the supra- and infrarostal cartilage unique to frog tadpoles) as well as the cranial muscles that attach to these cartilages. These new cartilage elements form a crucial part of a novel feeding apparatus, and the new arrangement of cranial muscles is necessary for their proper function. We have shown that the transcription factor FoxN3 is required for normal head morphogenesis, and also for proper heart development. Following morpholino knockdown of FoxN3, jaw cartilages are abnormal, and both cranial nerves and muscles are malformed. The expression of genes important for cartilage formation (Sox-9, Col2α1, Runx-2) is delayed. Joint markers were also down-regulated and bagpipe genes showed decreased expression at consecutive stages. Knock-downs of the bagpipe genes Bapx1 and Zax had very specific effects, such as the elimination of the jaw joint and the intermandibular joint, respectively. This indicates that these joints rather than the cartilages between them might be the real evolutionary novelties. Interestingly, upregulation of Bapx1 gave rise to ectopic mandibular arch cartilages that resemble cartilages produced repeatedly in the evolutionary history of frogs and present in several extant species. Finally, we tried to clarify if the malformations caused by FoxN3 knock-down are due to an evolutionarily conserved signalling pathway. Histone deacetylase-1 (HDAC-1) function during development was blocked by Trichostatin A (TSA)-treatment, which produced head malformations and loss of head structures in amphibian larvae. This indicates that HDAC forms an active complex with FoxN3 that binds to DNA. After knock-down of FoxN3, HDAC and its co-repressors Sin3 and RPD3 might not be able to bind to DNA and inhibit transcription. This would prevent cell cycle stop at the G2/M-phase checkpoint leading to reduced time for DNA repair and subsequent accumulation of DNA damage, which in the end causes malformations.
Projektbezogene Publikationen (Auswahl)
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(2011) A role for FoxN3 in the development of cranial cartilages and muscles in Xenopus laevis with special emphasis on the novel rostral cartilages. J. Anatomy 218, 226-242
Schmidt, J., Schuff, M. & Olsson, L.
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(2013) Cranial muscles in amphibians: Development, novelties and the role of cranial neural crest cells. J. Anatomy 222, 134-146
Schmidt, J., Piekarski N. & Olsson, L.
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(2017) The anatomy of the cranial and anterior spinal nerves in early tadpoles Xenopus laevis (Pipidae, Anura). J. Comp. Neur. 526, 836-857
Naumann, B. & Olsson, L.
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(2018) Bapx1 is required for jaw joint development in amphibians. Evolution & Development 20, 192-206
Lukas, P., & Olsson, L.
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(2018) Bapx1 upregulation leads to ectopic mandibular cartilage development in amphibians. Zoological Letters 4:16
Lukas, P., & Olsson, L.
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(2018) Sequence and timing of early cranial skeletal development in Xenopus laevis (Pipidae, Anura). J. Morphol. 279, 62-74
Lukas, P. & Olsson, L.
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(2019) FoxN3 is necessary for the development of the interatrial septum, the ventricular trabeculae and the muscles at the head/trunk interface in the African clawed frog Xenopus laevis (Lissamphibia: Anura: Pipidae. Developmental Dynamics 248, 323-336
Naumann, B., Schmidt, J. & Olsson, L.
