The role of ASCL1 and MYCN in human brain development

Informazioni relative al progetto

mAMBo

ID dell’accordo di sovvenzione: 841157

DOI

10.3030/841157

Progetto chiuso

Data della firma CE 8 Maggio 2019

Data di avvio 1 Maggio 2019

Data di completamento 30 Aprile 2021

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 212 933,76

Contributo UE

€ 212 933,76

Coordinato da

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom

Periodic Reporting for period 1 - mAMBo (The role of ASCL1 and MYCN in human brain development)

Periodo di rendicontazione: 2019-05-01 al 2021-04-30

Sintesi del contesto e degli obiettivi generali del progetto

The human brain has largely expanded throughout evolution, and this is linked to an increased intelligence and cognition. In comparison to other mammals, humans have the ability to generate a greater number of neurons during brain development, as a result of changes in neural progenitors’ activity. In humans, these cells show an increased and prolonged proliferation that allow to maximise the number of cell divisions which, ultimately, will result in a higher number of neurons. Disruptions in the proliferative ability of neural progenitors, mainly due to genetic mutations, can lead to abnormal brain development and impaired brain functions. Therefore, unravelling the basic mechanisms driving neural progenitor expansion in humans will contribute to understand the developing brain in health and disease. Previous research has identified human-specific genes that are expressed in neural progenitors and are associated with the expansion of the brain. In this project, we proposed a parallel approach to focus on a gene already known for its role in the mouse brain, MYCN, which also appears mutated in patients with brain disorders. We aimed to study MYCN function by eliminating it from stem cells and assessing the effect of its loss in neural progenitor’s ability to expand and to form neurons. In conclusion, this project identified a novel function of MYCN in human neural progenitors, providing new insights towards the understanding of the developing cortex and its greater expansion in humans.

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

Over two years, the project was divided into two main parts:

1) Firstly, identification of neural cell types expressing MYCN in both human foetal brains and cortical brain organoids to establish the expression pattern of MYCN during brain development in humans.
2) Secondly, human embryonic stem cells were grown in culture after removal of the MYCN gene, and consequently differentiated into neural progenitors and neurons, to see the effects of MYCN in neurogenesis, the process by which neurons are formed.

Work from part 1 produced a detailed analysis of MYCN expression during human neurogenesis at different developmental times. Results from part 2 demonstrated that MYCN contributes to neurogenesis by promoting the differentiation of neural progenitors into neurons. However, the absence of MYCN in human embryonic stem cells was associated with an increase of C-MYC expression, suggesting that another MYC gene could be taking over MYCN’s role in earlier stages of neurogenesis. Together, the project results have been explored in further research to determine how mutations in MYCN gene cause brain disorders and whether other MYC genes could be able to compensate for the loss of MYCN during neurogenesis. These findings have been reported to the research community informally prior to be being submitted for publication in a peer-reviewed scientific journal with open access, upon completion of the research project.

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)

In the course of the fellowship, I have optimised several state-of-art techniques relating to the manipulation and characterisation of neural cell types and I have established the brain organoid technology, which recreates different aspects of brain development and brain disorders. The results obtained represent an important advance in understanding the causes of brain disorders like intellectual disabilities or microcephaly (birth defect in which baby’s head is smaller than the average). The finding of compensatory actions from other genes of the same family provides a promising research avenue to explore how this could affect disease severity. Because there are no current cures for patients with such brain disorders, this research could provide an important social benefit.

The role of MYCN in the developing human brain