The smallest of the small: determining size through cell number

Projektinformationen

GrowCELL

ID Finanzhilfevereinbarung: 788093

DOI

10.3030/788093

Projekt abgeschlossen

EK-Unterschriftsdatum 18 Juni 2018

Startdatum 1 August 2018

Enddatum 31 Januar 2026

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 2 500 000,00

EU-Beitrag

€ 2 500 000,00

Koordiniert durch

THE UNIVERSITY OF EDINBURGH
United Kingdom

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

Berichtszeitraum: 2023-02-01 bis 2025-01-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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.