The smallest of the small: determining size through cell number

Informazioni relative al progetto

GrowCELL

ID dell’accordo di sovvenzione: 788093

DOI

10.3030/788093

Progetto chiuso

Data della firma CE 18 Giugno 2018

Data di avvio 1 Agosto 2018

Data di completamento 31 Gennaio 2026

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 2 500 000,00

Contributo UE

€ 2 500 000,00

Coordinato da

THE UNIVERSITY OF EDINBURGH
United Kingdom

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

Periodo di rendicontazione: 2023-02-01 al 2025-01-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.