The smallest of the small: determining size through cell number

Informations projet

GrowCELL

N° de convention de subvention: 788093

DOI

10.3030/788093

Projet clôturé

Date de signature de la CE 18 Juin 2018

Date de début 1 Août 2018

Date de fin 31 Janvier 2026

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 500 000,00

Contribution de l’UE

€ 2 500 000,00

Coordonné par

THE UNIVERSITY OF EDINBURGH
United Kingdom

Periodic Reporting for period 4 - GrowCELL (The smallest of the small: determining size through cell number)

Période du rapport: 2023-02-01 au 2025-01-31

Résumé du contexte et des objectifs généraux du projet

Determination of organismal size is a fundamental biological question. Vertebrate size is established based on total cell number generated during development. Despite the 75 million-fold difference in size between the smallest and largest mammals, the mechanisms for this remain to be determined.

Over the last decade our study of extreme growth disorders has identified 18 new human disease genes. We established that these genes encode core components of the cell-cycle machinery, providing cellular and developmental insights into the pathophysiological mechanisms of these disorders. From our starting point of human disease, this approach also revealed novel genome instability genes informing fundamental research of basic biological processes. Still, the molecular basis for over half of individuals with microcephalic dwarfism remains unknown.

This program seeks to identify novel growth regulating genes and gain insight into how total cell number is determined in both pathological and physiological states.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

This project is applying Whole Genome Sequencing to our patient cohort to achieve screen saturation via identification of coding and non-coding mutations, and this has led to the publication of 6 new human disease genes during the project to date. Forward-genetic genome-wide CRISPR screens have been established in the lab and will be applied to developmentally relevant systems to define key cellular processes impacting human growth. Beyond these ‘discovery science’ approaches, cellular and model organism techniques are being used to define the mechanistic basis for human disease caused by mutations in core replication machinery and DNMT3A, a key epigenetic factor.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

By the completion of this project, we aim to establish a subset of microcephalic dwarfism genes as growth regulators, and thereby further define when and how organism size is determined. As well, we anticipate that these studies will link essential cellular machinery governing proliferation with human disease, identify novel genome stability factors and potentially yield insights into the developmental regulation of mammalian size.