PUBLICATIONS:
We have defined a novel and necessary function for the cytoplasmic translation regulatory actions of the multifaceted SRSF1 protein in vivo (Malson, Hayward, Yeyati et al eLife 2021). We show this factor plays essential roles in motile cilia function and postnatal survival in mice. Importantly, this study independently confirms the central hypothesis of CiliaCircuits, involving SRSF1, in part of the highly dynamic and compartmentalized post-transcriptional regulation of motile ciliogenesis. This collaboration has allowed us to improve our workflows with limiting biological inputs, like primary tracheal cultures for OMICs analysis, as detailed in WP1 and WP3.
As part of collaboration with the Pigino lab (MPI CBD), we have used similar systems approaches to biochemically define native macromolecular IFT complexes as well as spatially define them in situ with correlative electron microscopy on endogenous ciliary ultrastructures (Quidwai et al eLife 2021) in primary cells from control and mutant mice. This collaboration has been useful to working towards tenets in WP3 to spatially define position of translational factories in time (super-resolution live imaging) and space (CLEM) in motile ciliated cells This work demonstrates a key strength of our group - effectively moving across biological scales, from human disease gene candidates through mechanism to defining molecules in cellular space.
Evidence for post-transcriptional control of cilia gene expression is best characterized by tubulin autoregulation where levels of tubulin mRNA are sensitive to the concentration of the soluble tubulin heterodimer via a co-translational RNA degradation mechanism (WP1). We had used ‘tubulin’ as the exemplar for the best understood regulatory circuit in terms of cellular feedback loops in the proposal and interview for CiliaCircuits. What we had not imagined at the time was that we would uncover a single tubulin isotype which plays and essential and non-redundant role in building motile cilia axonemes. We used next generation sequencing on a cohort of 11 patients with the motile ciliopathy primary ciliary dyskinesia (PCD). We find recurrent and de novo mutations in TUBB4B which cluster on distinct surfaces on and within the beta-tubulin subunit (Mechaussier et al. medRXiv 2022). Our data supports isotype-specific requirements at an organelle-level. Using both patient-derived cells and KI mouse models, we demonstrate other cytoskeletal processes appear unperturbed highlighting the specific dominant-negative effects of TUBB4B disease variants on centrioles and cilia. Using Tubb4b knock-out mice we demonstrate that this requirement for TUBB4B is essential and non-redundant with any of the other 8 beta-isotypes expressed in mice.Our innovative and highly collaborative cross-disciplinary study showcases how rare disease genetics can inform on highly fundamental cellular processes and why understanding disease mechanisms sheds light on cellular regulatory circuits, and provides insight into how we must work to ‘fix broken genes’ and whether diseases are reversible.
We have gained fundementtal insight into how cells regulate and remodel local proteomes. Centriolar satellites are large protein assemblies that orbit the centrioles and are made of a scaffold composed of the protein PCM1. In culture, they are essential for duplicating centrioles and forming cilia. The roles for PCM1 in different tissues of the body and during development remained unclear. To test this, we generated mice which lack all PCM1. Mutant mice were born but often died within the first few days of birth, showing features of ciliopathies- a group of genetic diseases arising from defects in the structure or function of cilia. These include hydrocephaly (fluid build-up in the brain ventricles) and infertility. While we confirmed that all tissues expressed PCM1 and mutant mice show disruption of satellites in all tissues, we only observed effects on ciliogenesis (cilia formation) in certain tissues, most frequently those with motile cilia. Our work demonstrates that PCM1-dependent centriolar satellites promote efficient trafficking and turnover of proteins to and from centrioles to support ciliogenesis including dynein motor proteins. Centriolar satellites thus play key roles in vivo in remodelling local proteomes, including controlling proteostasis, in order to regulate timely ciliogenesis (WP1).
As a thought leader in the cilia field, we are regularly asked to write opinion pieces on emerging research (Wachten D, Mill P. The cilia mechanosensation debate gets (bio)physical. Nat Rev Nephrol. 2023 Mar 13. doi: 10.1038/s41581-023-00701-4) and the state-of-play of the cilia field (Mill P, Christensen ST, Pedersen LB. Primary cilia as dynamic and diverse signalling hubs in development and disease. Nat Rev Genet. 2023 Apr 18. doi: 10.1038/s41576-023-00587-9) with more commissioned for 2023.
POLICY AND ENGAGEMENT: We have actively engaged with government, funders, industry and patient advisory groups in the first 30 months of CiliaCircuits. We are a partner in the H2020 EuroGCT (€2M, 2021-2026) for public dissemination and engagement with emerging cell and genome therapies. We present regularly and facilitate visits with branches of PCD UK (05/21) and their Medical Board (05/22). I was an invited panellist in the CZI Advancing Diagnosis in Rare Disease workshop (06/21) and subsequent funding call. I was an invited speaker at Pfizer’s Virtual Frontiers in Human Disease Symposium on ciliopathies (05/22). From the start of 2022, I have been on the Science Advisory Board for UMIB (Unit for Multidisciplinary Research in Biomedicine), University of Porto, Portugual and since 01/2023 a member of the Scientific Advisory Board for PCD Research. As part of EMBO Cilia2022 Meeting, I helped organize and run the satellite Patient Day for ciliopathy patients, their families and patient advocacy groups from across Europe in Cologne, DE (03/10/2022), which reached an audience of 75 attendees. I also helped organize and run CiliaInterconnect which ran in parallel to EMBO Cilia2022 Meeting (Cologne, DE)- a networking initiative and event funded by European Join Programme Rare Diseases (EJP RD), to bring together clinicians, patients, and researchers from countries that are typically underrepresented including Turkey and Eastern Europe to foster better integration and extend interactions between patients, physicians, and scientists in the European ciliopathy space.
LEADERSHIP:
I am a founding member of the UK Cilia Network Executive Committee (2015 – current). I organize and host a regular e-symposium series (BSCB GenSoc UK Cilia Network e-symposia) throughout the pandemic reaching >1250 international registrants, which brings together international emerging talent with established experts, across organisms and disciplines. I organize key international cilia sceintific meetings: FASEB (2019, 2024-26-28), EMBO (2022) and GRC (2023/25), as well as PCD Foundation Scientific meeting (2021) and EMBO Dynein workshop (2021).
