Interview with Guest Editor Lotte Pedersen

Lotte Pedersen

What are your research interests?

Our overarching goal is to understand the molecular mechanisms that govern the assembly, disassembly and function of primary cilia in coordinating cellular signalling networks across various cellular and developmental contexts. We also aim to investigate how these mechanisms are disrupted in cilia-related diseases, known as ciliopathies. I run my lab jointly with my close colleague and long-time collaborator, Søren T. Christensen.

What attracted you to the field of cilia biology?

My PhD research focused on histone-like proteins in the bacteria Chlamydia trachomatis. Afterwards, I did a postdoc with Peter Setlow at UConn Health Center (Farmington, Connecticut, USA) where I studied penicillin-binding proteins in Bacillus subtilis. My main goal was to identify and characterise the subcellular localisation of a protein called PBP1. Despite the technical challenges, we successfully visualised PBP1 at the division septum of B. subtilis and I became fascinated by the potential to visualise and pinpoint proteins within cells to better understand cellular mechanisms. As bacteria seemed at the time too small to allow more detailed exploration, I decided to study eukaryotic cells. This shift in focus led me to pursue a second postdoc. Also, at the time, I was pregnant and felt that starting a research group or taking on a permanent position would be difficult while caring for my daughter. Therefore, I contacted Joel Rosenbaum at Yale University (USA), who was doing pioneering work on cilia and flagella using Chlamydomonas, a biflagellate alga, as a model to study cilia assembly mechanisms. He had published landmark papers including a 1993 study with his former PhD student, Keith Kozminski, in which they discovered intraflagellar transport (IFT). Later in 1998, Joel and Doug Cole (a former postdoc) isolated IFT particles and identified peptide sequences, revealing that IFT proteins were essential for cilia formation. Interestingly, some of these proteins were homologous to those involved in cilia formation in C. elegans. Just after I joined the laboratory, Joel together with Greg Pazour and George Witman (University of Massachusetts Chan Medical School, USA) demonstrated that mutations in Ift88, an IFT gene, led to defective primary cilia in mouse kidney, explaining why these mice develop polycystic kidney disease (PKD). After this discovery, the field quickly expanded as scientists recognised that primary (non-motile) cilia play crucial roles in vertebrate development and disease. Before 2000, primary cilia were thought to have minimal functions, unlike motile cilia, which were known to play major roles in many contexts, like airway health. Since then, our understanding of the essential role of primary cilia has dramatically grown. It was an inspiring time to begin working on cilia, and I was completely captivated.

What questions is your lab trying to answer just now?

The kidney is a major organ that is affected by ciliopathies and most of our current work focuses on understanding the role of primary cilia in kidney epithelial cells. We have several projects underway to address key questions. In collaboration with Stine F. Pedersen (University of Copenhagen, Denmark), a colleague who studies pH-regulatory mechanisms, we are investigating how intraciliary pH is regulated. Coincidentally, her laboratory recently discovered that the pH-regulator and co-transporter NBCn1 localises to cilia and published this finding in JCS. Around the same time, we found that NBCn1 interacts with a ciliary protein that we study, prompting us to join forces to explore how NBCn1 affects ciliary pH regulation and its impact on signalling. In another project, we are studying intraciliary movement associated with non-canonical IFT motor proteins. Previously, we reported that a kinesin-3 motor, KIF13B, localises to cilia, moves in a burst-like fashion and regulates the ciliary localisation of the G-protein-coupled receptor Smoothened, which in turn controls Hedgehog signalling. We now aim to characterise KIF13B movement in greater detail using single-molecule approaches and to investigate its coordination with conventional IFT in cilia. Our work on KIF13B also led us to study extracellular vesicles (EVs), which have recently been discovered to be released not only from the cell body but also from cilia – a relatively new concept in cilia research. We suspect that KIF13B plays a role in regulating EV release from cilia, and that these EVs help cilia expel excess material, as suggested by studies in several ciliated organisms, ranging from Chlamydomonas to C. elegans and mouse. In addition, cilia-derived EVs might facilitate intercellular signalling. For example, the laboratory of Maureen Barr (Rutgers University, USA) has shown that in C. elegans, EVs shed from male sensory neuronal cilia are crucial for intercellular signalling and male mating behaviour. In mammalian cells, the laboratory of Max Nachury (University of California San Francisco, USA) among others, has demonstrated that the actin cytoskeleton is crucial to ciliary EV release, but many questions remain. I am part of a European Union-funded consortium, Therapeutics for Renal Ciliopathies (TheRaCil), coordinated by Sophie Saunier (Institut Imagine, France). This consortium aims to develop treatments for kidney-related ciliopathies. As part of this effort, our lab is examining how gene mutations linked to kidney ciliopathies affect EV release from cilia. Finally, in collaboration with my colleagues Jakob G. Knudsen and Søren T. Christensen, we are studying the role of primary cilia in glucagon secretion, which is mediated by alpha cells in the pancreatic islets. For this we are using cultured cells as well as mouse models.

What recent discoveries do you find exciting and where do you think cilia biology is heading?

This is a challenging question to answer, as there have been so many exciting discoveries in cilia research. Having been in the field for nearly 25 years, I've witnessed exponential growth, driven in particular by advances in imaging, ’omics and structural biology. Despite this progress, many questions and challenges remain. One fascinating aspect to explore is the diversity and complexity of cilia across organisms, cell types and tissues. As we study more ciliated cells, we are seeing just how varied cilia are. Understanding the reasons behind this diversity will be a major focus in the future. Emerging technologies like cilia-targeted proximity labelling and spatial proteomics, pioneered by researchers like David Mick (Saarland University Medical School, Germany) and Max Nachury, are enabling us to analyse cilia proteomes across different cellular contexts. The next step is to uncover the molecular basis for and functional consequences of this diversity. From a human disease perspective, recent discoveries are bringing us closer to developing treatments for ciliopathies. For example, our TheRaCil consortium is working toward this goal, and the laboratory of Sophie Saunier recently published a promising study showing that agonists of prostaglandin receptors can ameliorate certain ciliopathy phenotypes. Similar developments are emerging from other laboratories as well. Personally, I'm particularly interested in unconventional IFT motors, such as kinesin-3 motors, which might contribute to the structural and compositional diversity of cilia seen in multicellular organisms. Another intriguing area, as I mentioned earlier, is the release of EVs from cilia. Although this is still a new topic for us, I am closely following the literature to understand the mechanisms and functions of these vesicles, as they could play significant roles in intercellular signalling.

Why did you accept the invitation to become a Guest Editor for this issue?

That's a great question. I accepted this invitation for several reasons. First, I have always appreciated JCS. Over the years, I've published several papers in JCS and had positive experiences as both an author and a reviewer. I also value that JCS is a society-driven, not-for-profit journal published by The Company of Biologists, an organisation I admire for its commitment to the scientific community. This organisation actively supports the field by sponsoring meetings and workshops – I organised a European Molecular Biology Organisation (EMBO) workshop on cilia in Copenhagen in 2018 thanks to funding from The Company of Biologists, for which I am very grateful. I also appreciate their ‘Forest of Biologists’ biodiversity initiative, which I'm eager to support. When I received the invitation from Michael Way to serve as co-editor, I was delighted to learn that Pleasantine Mill (University of Edinburgh, UK) was also invited. I look forward to working with her; we've met a few times, and we recently co-authored a Review article, so collaborating with her on this Special Issue on ‘Cilia and Flagella: from Basic Biology to Disease’ is something I am genuinely excited about.

What impact would you like to make in this role?

I've given this some thought, and here's an (not-so) unconventional answer: I'd love to see more cilia-related publications in JCS, which would also contribute to the Forest of Biologists initiative by planting more trees! I hope to encourage my colleagues in the field to submit their latest work to JCS. Earlier this year, I attended two cilia and flagella conferences where the research presented was incredibly exciting. Together with Pleasantine, I'm looking forward to facilitating the publication of some groundbreaking new studies in the cilia and flagella fields.

What do you hope to get out of this role?

I have some editorial experience as a Reviewing Editor for other scientific journals, so I'm familiar with the manuscript assessment process. As a Guest Editor, I look forward to collaborating with Pleasantine Mill, as well as with the editorial staff and board members of JCS, to further broaden my editorial experience. Together, I hope we can create a Special Issue that features an exciting collection of papers showcasing the latest research on cilia and flagella – appealing not only to the cilia and flagella communities but also to the broader JCS readership.

What will be your role in handling manuscripts for Journal of Cell Science?

We'll review incoming manuscripts, assess their suitability and decide whether to send them out for peer review. Pleasantine Mill will likely handle manuscripts with a focus on ciliopathies or developmental biology, while I'll focus on those related to cellular and molecular mechanisms. After an initial assessment, we'll select reviewers, gather feedback and determine each manuscript's suitability for publication, providing feedback on any required revisions. Although I have relevant experience as a reviewer, I'm excited to learn more about JCS's editorial approach.

What do you think will be the most challenging aspect?

One challenge I anticipate is managing the wide range of topics within the rapidly expanding cilia and flagella fields. There might be instances when I encounter topics outside my expertise, which could be challenging. Securing reviewers might also pose difficulties. Although I haven't had major issues with this before, I recognise that the demand for reviewers has been rising, so it could require extra effort. Another challenge will be declining manuscripts that don't meet the journal's standards. Although rejecting work can be difficult, my priority is to maintain high scientific quality. For me, the criteria are clear – research must be high-quality and offer novel insights. Even if a study isn't groundbreaking, it deserves consideration if it contributes valuable insights and meets rigorous quality standards.

Could you mention a few broad themes you expect to emerge from this Special Issue?

Broadly, I expect to see papers using high-resolution imaging, including expansion microscopy, which is an exciting development in the cilia field. I also anticipate studies on sub-ciliary protein localisation, diversity of cilia across organisms and tissues, signalling pathways and the molecular basis of ciliopathies, such as characterisation of missense variants and their cellular impacts. Additionally, I hope to see research on EVs and new methodologies that will benefit the broader field of cilia research. The diversity of the field, combined with emerging tools and insights into signalling, makes it an exciting and rapidly expanding area.

When you're not a Guest Editor or doing research, what are the things you do for fun?

That's a great question! I'm really into outdoor activities and sports, especially hiking and mountain biking, which I enjoy with my partner and family. Although Denmark lacks mountains, we have plenty of forests and coastlines, so I'm out on my bike almost every weekend when the weather allows. Until a few years ago, I played handball, which is very popular in Denmark. However, as I got older, I decided to stop to reduce the risk of injury. I still occasionally meet up with my former teammates and follow my favourite team on TV – I can get quite passionate, even a bit obsessive, about their scores, which my partner finds both amusing and a little annoying. I inherited my love for handball from my dad, who is nearly 88 years old and still active in sports – he now plays golf. Sports have always been a big part of my life and I've enjoyed trying different activities since childhood.

Lotte Pedersen was interviewed by Sara Morais da Silva, Reviews Editor for Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.