The smallest of the small: determining size through cell number

Información del proyecto

GrowCELL

Identificador del acuerdo de subvención: 788093

DOI

10.3030/788093

Proyecto cerrado

Fecha de la firma de la CE 18 Junio 2018

Fecha de inicio 1 Agosto 2018

Fecha de finalización 31 Enero 2026

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 2 500 000,00

Aportación de la UE

€ 2 500 000,00

Coordinado por

THE UNIVERSITY OF EDINBURGH
United Kingdom

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

Período documentado: 2023-02-01 hasta 2025-01-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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.