Pleasantine Mill

Genetics of cilia biology.

Prof Pleasantine Mill is an MRC Investigator at the MRC Human Genetics Unit at the University Edinburgh’s Institute for Genetics and Cancer where she leads a programme to understand genetic disease and disease mechanisms arising from dysfunction of mammalian cilia, called the ciliopathies. With 25+ years of expertise in developmental genetics and cell biology, her work spans from forward genetics screens through to candidate discovery in human disease genetics. Her lab focuses on phenotype-driven projects which disrupt cilia structure and/or function to undercover underlying genetic changes, understand disease mechanisms and move towards much needed therapeutics for rare diseases. Her novel in vivo work can be summed up as ‘cell biology on an organismal scale’. 

portrait photo of Pleasantine Mill
Pleasantine Mill

Her lab harnesses quantitative imaging across biological scales (from light microscopy through to electron microscopy) to understand how different types of mammalian cilia are assembled and maintained, and how they are disrupted by disease-causing mutations. Her work is funded by the UK Medical Research Council, Wellcome, NIHR, LifeArc and the European Research Council.

Dr Marina Armpi, Ms Chloe Brotherton, Dr Emma Hall, Dr Rasmus Hejlesen, Mr Adam Hetherington, Dr Carlos López Solarat, Dr Roly Megaw, Ms Sreeja Mitra, Dr Jana Muronova, Ms Sophie Nakford, Dr Fay Newton, Ms Linda Nguyen, and Dr Patricia Yeyati 


Cilia are tiny, hair-like structures that extend from the surface of nearly every cell in our body. Though small, they perform critical functions—acting as cellular antennae that sense the environment and, in some cases, generating important fluid flows within our bodies. When cilia don't work properly, the consequences can be devastating. Ciliopathies—genetic disorders affecting cilia structure or function—can cause birth defects, blindness, intellectual disability, kidney failure, and infertility. While we know hundreds of genes are involved in building and maintaining cilia, we understand surprisingly little about how specific genes control different ciliary functions across the diverse array of cell types in our bodies.

Our lab combines cutting-edge genetics with advanced molecular and cellular biology to answer fundamental questions:

  • How do cells build the basic machinery needed for cilia to function?
  • How is this core program adapted for specialized tasks, like the coordinated beating of cilia in our airways?
  • What can gene variants causing human disease teach us about how cilia work?
  • Can we use "genome surgery" to fix broken genes—and are ciliopathies reversible?

Our Approach

Discovering new genes: We use powerful genetic screens—both forward genetics in animals and cell-based models—to identify genes essential for cilia function and understand what happens when they fail.

Understanding human disease: Working closely with clinical genetics partners, we identify disease-causing changes in DNA, or pathogenic variants, in ciliopathy patients. Using CRISPR genome editing, we recreate these variants in the lab to understand exactly how they disrupt cilia function. By integrating advanced microscopy, transcriptomics, and proteomics, we're building a comprehensive picture of disease mechanisms—knowledge that could lead to better clinical care and potential treatments.

Seeing cilia in action: Cilia are tiny and dynamic, making them challenging to study. We're developing innovative imaging approaches using confocal, super-resolution, and electron microscopy to capture ciliary events with unprecedented detail across time and space.

Developing genome-based therapies: We're pioneering methods to understand how different cells respond to genome editing—a crucial step toward using this technology therapeutically. Our novel genome editing reporters track editing events in real time, helping us optimize strategies for correcting genetic diseases like ciliopathies directly in patients.

Through this multifaceted approach, we're working toward a future where ciliopathies can be not only managed, but potentially cured.


fluorescence image of cilia (red)

Megaw R, Moye A, Zhang Z, Newton F, McPhie F, Murphy LC, McKie L, He F, Jungnickel MK, von Kriegsheim A, Tennant PA, Brotherton C, Gurniak C, Gross AK, Machesky LM, Wensel TG, Mill P. Ciliary tip actin dynamics regulate photoreceptor outer segment integrity. Nat Commun. 2024 May 21;15(1):4316. doi: 10.1038/s41467-024-48639-w. PMID: 38773095; PMCID: PMC11109262.

Dodd DO, Mechaussier S, Yeyati PL, McPhie F, Anderson JR, Khoo CJ, Shoemark A, Gupta DK, Attard T, Zariwala MA, Legendre M, Bracht D, Wallmeier J, Gui M, Fassad MR, Parry DA, Tennant PA, Meynert A, Wheway G, Fares-Taie L, Black HA, Mitri-Frangieh R, Faucon C, Kaplan J, Patel M, McKie L, Megaw R, Gatsogiannis C, Mohamed MA, Aitken S, Gautier P, Reinholt FR, Hirst RA, O'Callaghan C, Heimdal K, Bottier M, Escudier E, Crowley S, Descartes M, Jabs EW, Kenia P, Amiel J, Bacci GM, Calogero C, Palazzo V, Tiberi L, Blümlein U, Rogers A, Wambach JA, Wegner DJ, Fulton AB, Kenna M, Rosenfeld M, Holm IA, Quigley A, Hall EA, Murphy LC, Cassidy DM, von Kriegsheim A; Scottish Genomes Partnership; Genomics England Research Consortium; Undiagnosed Diseases Network; Papon JF, Pasquier L, Murris MS, Chalmers JD, Hogg C, Macleod KA, Urquhart DS, Unger S, Aitman TJ, Amselem S, Leigh MW, Knowles MR, Omran H, Mitchison HM, Brown A, Marsh JA, Welburn JPI, Ti SC, Horani A, Rozet JM, Perrault I, Mill P. Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules. Science. 2024 Apr 26;384(6694):eadf5489. doi: 10.1126/science.adf5489. Epub 2024 Apr 26. Erratum in: Science. 2024 May 10;384(6696):eadq2178. doi: 10.1126/science.adq2178. PMID: 38662826; PMCID: PMC7616230.

Waddell SH, Yao Y, Olaizola P, Walker A, Jarman EJ, Gournopanos K, Gradinaru A, Christodoulou E, Gautier P, Boerrigter MM, Cadamuro M, Fabris L, Drenth JP, Kendall TJ, Banales JM, Khamseh A, Mill P, Boulter L. A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease. Sci Transl Med. 2023 Sep 13;15(713):eabq5930. doi: 10.1126/scitranslmed.abq5930. Epub 2023 Sep 13. PMID: 37703354; PMCID: PMC7615241.

Hall EA, Kumar D, Prosser SL, Yeyati PL, Herranz-Pérez V, García-Verdugo JM, Rose L, McKie L, Dodd DO, Tennant PA, Megaw R, Murphy LC, Ferreira MF, Grimes G, Williams L, Quidwai T, Pelletier L, Reiter JF, Mill P. Centriolar satellites expedite mother centriole remodeling to promote ciliogenesis. Elife. 2023 Feb 15;12:e79299. doi: 10.7554/eLife.79299. PMID: 36790165; PMCID: PMC9998092.

Haward F, Maslon MM, Yeyati PL, Bellora N, Hansen JN, Aitken S, Lawson J, von Kriegsheim A, Wachten D, Mill P, Adams IR, Caceres JF. Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function. Elife. 2021 Aug 2;10:e65104. doi: 10.7554/eLife.65104. PMID: 34338635; PMCID: PMC8352595.

 


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