"Deciphering how centrosome dysfunctions lead to microcephaly (2017-06-MARTHIENS-BASTO)" project details

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General information

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2017-06-MARTHIENS-BASTO

Centrosomes, Chromosome number alterations, Microcephaly, Mitotic spindle morphogenesis/positioning, Neural stem cells

Deciphering how centrosome dysfunctions lead to microcephaly

Director(s) and team

Veronique Marthiens

Biology of centrosomes and cilia

Abstract

Description of the PhD thesis project
We investigate the biology of centrosomes, the main microtubule (MT)-organizing centers in animal cells, and how mutations in centrosome genes result in a broad range of pathological conditions including cancer and microcephaly (reduced brain size). We use several model systems like Drosophila, mouse, primary and transformed cells in culture, and human tissues.

These different model systems are combined with molecular and biochemical approaches and state-of-the art cell biology techniques such as confocal, spinning disk and high-resolution microscopy combined with qualitative and quantitative image analysis.

This PhD project addresses a timely and fundamental question in cell and developmental biology: how does the MT cytoskeleton influence brain size and cognitive capacity. We have characterized the MT cytoskeleton and mitotic spindle assembly in the developing wild type (WT) mouse neo-cortex (D. Vargas et al, in preparation). We have identified differences in the mechanisms of spindle morphogenesis and more importantly, a biomechanical contribution of the cell cortex to MT spindle morphogenesis. This PhD project will rely on the expertise and results obtained in WT mice to translate these findings in two validated mouse models of microcephaly:
1) model with extra centrosomes through the over-expression of Plk4;
2) model with reduced centrosome number through mutations in CPAP.
This will be achieved through an established collaboration with Dr Gergely (Cambridge University, UK). In addition to different imaging approaches, this project will also use computer biology methods and dedicated algorithms to quantitatively characterize spindle morphogenesis and outcome of cell division in mutant conditions. This part of the project will be developed in collaboration with Dr Racine (QuantaCell, Fr).

This project will generate novel concepts that will contribute to understand the etiology of MCPH and most likely impact on the comprehension of other growth disorders.

International, interdisciplinary & intersectoral aspects of the project
The project is at the interface between cell biology and computer biology. The PhD student will collaborate with the lab of F. Gergely (University of Cambridge, UK) expert in centrosomes and MCPH disorders. Her group will contribute with mouse MCPH models and expertise for whole genome sequencing. The student will visit this lab and will receive regular mentoring. The student will also collaborate with the computer biologist V. Racine from QuantaCell (Bordeaux, France) for data analysis. New algorithms will be developed to allow extraction of a variety of spindle morphometry parameters from 3D-reconstructions. The student will be trained for image and computational analysis and participate in the design and validation of algorithms.

Recent publications
1. Serçin Ö, Larsimont JC, Karambelas AE, Marthiens V, Moers V, Boeckx B, Le Mercier M, Lambrechts D, Basto R, Blanpain C. Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nat Cell Biol. 2016 Jan;18(1):100-10.
2. Sabino D, Gogendeau D, Gambarotto D, Nano M, Pennetier C, Dingli F, Arras G, Loew D, Basto R. Moesin is a major regulator of centrosome behavior in epithelial cells with extra centrosomes.
Curr Biol. 2015 Mar 30;25(7):879-89.
3. Gogendeau D, Siudeja K, Gambarotto D, Pennetier C, Bardin AJ, Basto R. Aneuploidy causes premature differentiation of neural and intestinal stem cells. Nat Commun. 2015 Nov 17;6:8894.
4. Rujano MA, Sanchez-Pulido L, Pennetier C, le Dez G, Basto R. The microcephaly protein Asp regulates neuroepithelium morphogenesis by controlling the spatial distribution of myosin II. Nat Cell Biol. 2013 Nov;15(11):1294-306.
5. Marthiens V, Rujano MA, Pennetier C, Tessier S, Paul-Gilloteaux P, Basto R. Centrosome amplification causes microcephaly. Nat Cell Biol. 2013 Jul;15(7):731-40.

Requirements to apply for the PhD thesis project

Applicants should be highly motivated to explore cell biology questions within the in vivo context of the mouse embryonic brain. Background in cell biology, stem cell biology and/or developmental biology is advantageous. The project is based on microscopy approaches of fixed and live tissue samples and will require state-of-the art image analysis. The applicant should have either experience or a strong motivation to learn image and computational analysis. Basic knowledge in informatics and mathematics would therefore be a plus but not compulsory.