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Notch/Her12 signalling modulates, motile/immotile cilia ratio downstream of Foxj1a in zebrafish left-right organizer
Publication . Tavares, Barbara; Jacinto, Raquel; Sampaio, Pedro; Pestana, Sara; Pestana, Sara; Pinto, Andreia; Vaz, Andreia; Roxo-Rosa, Mónica; Gardner, Rui; Lopes, Telma; Schilling, Britta; Henry, Ian; Saúde, Leonor; Lopes, Susana Santos; Centro de Estudos de Doenças Crónicas (CEDOC); NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); eLife Sciences Publications
Foxj1a is necessary and sufficient to specify motile cilia. Using transcriptional studies and slow-scan two-photon live imaging capable of identifying the number of motile and immotile cilia, we now established that the final number of motile cilia depends on Notch signalling (NS). We found that despite all left-right organizer (LRO) cells express foxj1a and the ciliary axonemes of these cells have dynein arms, some cilia remain immotile. We identified that this decision is taken early in development in the Kupffer’s Vesicle (KV) precursors the readout being her12 transcription. We demonstrate that overexpression of either her12 or Notch intracellular domain (NICD) increases the number of immotile cilia at the expense of motile cilia, and leads to an accumulation of immotile cilia at the anterior half of the KV. This disrupts the normal fluid flow intensity and pattern, with consequent impact on dand5 expression pattern and left-right (L-R) axis establishment.
Dynamics of cilia length in left–right development
Publication . Pintado, P.; Sampaio, P.; Tavares, B.; Montenegro-Johnson, T.D.; Smith, D.J.; Lopes, S.S.; Centro de Estudos de Doenças Crónicas (CEDOC); NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Royal Society
Reduction in the length of motile cilia in the zebrafish left– right organizer (LRO), also known as Kupffer’s vesicle, has a large impact on left–right development. Here we demonstrate through genetic overexpression in zebrafish embryos and mathematical modelling that the impact of increased motile cilia length in embryonic LRO fluid flow is milder than that of short cilia. Through Arl13b overexpression, which increases cilia length without impacting cilia beat frequency, we show that the increase in cilium length is associated with a decrease in beat amplitude, resulting in similar flow strengths for Arl13b overexpression and wild-type (WT) embryos, which were not predicted by current theory. Longer cilia exhibit pronounced helical beat patterns and, consequently, lower beat amplitudes relative to WT, a result of an elastohydrodynamic shape transition. For long helical cilia, fluid dynamics modelling predicts a mild (approx. 12%) reduction in the torque exerted on the fluid relative to the WT, resulting in a proportional reduction in flow generation. This mild reduction is corroborated by experiments, providing a mechanism for the mild impact on organ situs. ©2017 The Authors.
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH/BPD/77258/2011