PhD position in Developmental Biology/Bioinformatics (Paris) (M/F)

Job Description

Thesis Subject

State of the art
The cerebellum is essential in all jawed vertebrates for motor coordination and higher cognitive functions. Cerebellar neurons arise from two main germinative zones: the ventricular zone and the upper rhombic lip (URL), a specialized neural stem cell (NSC) niche. Recent studies have revealed key aspects of human rhombic lip (hRL) organization and shown that defects in its development underlie several human syndromes. These findings challenge the traditional rodent-centric view of URL development and emphasize the need for alternative experimental models, and a deeper understanding of the gene regulatory networks governing URL cell trajectories.
T Cell Factors (TCFs) are central transcription factors (TFs) of the canonical Wnt signaling pathway. TCF activity, together with expression of the proneural repressors Hairy and Enhancer of Split (Hes/Hey), constitutes a hallmark of NSC self-renewal. Although TCF activity and Hes/Hey transcripts are detected in the URL across species, their precise functions and regulatory interactions within the cerebellar rhombic lip remain poorly understood. Our work identifies amphibians as a relevant model to study vertebrate URL development and demonstrates that BARHL transcription factors inhibit TCF activity and influence URL cell fate decisions, potentially through interactions with TCF and HES proteins.
Objectives
During this PhD, we will combine developmental biology, multi-omics, and bioinformatics approaches using amphibian embryos. Our objectives are:
1. to define transcriptomic profiles, conserved cell-state markers, and gene expression trajectories during early cerebellar development in amphibians using single-nucleus (SN) RNA-seq and SN ATAC-seq, and to compare these data with mammalian datasets, including rodents, humans, and human cerebellar organoids;
2. to determine how altered TCF activity affects cellular differentiation and progression in the URL/external granular layer (EGL), including its role in cell fate specification, chromatin remodeling, and progenitor maintenance.

Your Work Environment

The PhD will be performed under the supervision of BC Durand (0000-0002-0047-288X) CRHC CNRS a principal investigator leading her own research in embryology, signaling, and transcriptional regulation. BC. Durand previous work has been instrumental in elucidating Barhl activities and pathways in Xenopus early brain development; Together with 4 other teams she created a new group (NeAR) that is part of a the Dev2A Unit of IBPS starting January 2025. She has established amphibian as a relevant model to study cerebellar development.
All necessary technological expertise in molecular and cellular biology, and developmental embryology, is available. The wet part of the project will be done at the IBPS, and preliminary data demonstrated the feasibility of the project. Indeed, our team has extensive experience in X. laevis embryo dissection, including that of the cerebellar anlage, and cerebellar alterations of TCF activity through modulating BarHl1 levels. Single nuclei will be encapsulated using the 10x Genomics Chromium platform. Two cDNA libraries will be generated: one for 3′ SN RNA sequencing and one for SN ATAC-seq. Sequencing will be performed using short-read, paired-end sequencing, with sufficient depth to detect approximately 3,500–4,000 genes per nucleus. All experimental steps, including sequencing, alignment to the X. laevis v10.1 genome, and quality control, will be carried out by the Curie Institute platform (responsible scientists: Charlene Lasgi and Leanne De Koning).
The bioinformatics part will be done at the IBPS with the PhD student in collaboration with M Doulazmi, IR CNRS (0000-0002-0313-1490) an expert in bioinformatic/biostatistical analysis (CNRS UMR8265, NeuroSU - IBPS - SU). It will benefit from a collaboration with O. Saulnier (0000-0003-4111-1017) a team leader at Curie Institute with expertise in the analysis of large-scale genomic data and in particular the spatial and molecular organization of the human URL. His team is entirely computational and aims at decoding the cellular hierarchies and trajectories of the human hindbrain development to identify and characterize developmental programs hijacked in pediatric brain tumors. We will hire a 2 years bioinformatics engineer (ANR funds) dedicated to the project. The engineer will be on the Institut Curie bioinformatics platform (resp: Nicolas Servant) and benefit from their multi-omics and cross species trajectories expertise. If necessary, the student will receive necessary training for SN-seq and SN(ATAC)-seq transcriptomic analysis through tutoring by the Inforbio platform (IBPS)(resp: Lorette Noiret).

Constraints and risks

The PhD will be performed under the supervision of BC Durand (0000-0002-0047-288X) CRHC CNRS a principal investigator leading her own research in embryology, signaling, and transcriptional regulation. BC. Durand previous work has been instrumental in elucidating Barhl activities and pathways in Xenopus early brain development 1–3,7; Together with 4 other teams she created a new group (NeAR) that is part of a the Dev2A Unit of IBPS starting January 2025. She has established amphibian as a relevant model to study cerebellar development.
All necessary technological expertise in molecular and cellular biology, and developmental embryology, is available. The wet part of the project will be done at the IBPS, and preliminary data demonstrated the feasibility of the project. Indeed, our team has extensive experience in X. laevis embryo dissection, including that of the cerebellar anlage, and cerebellar alterations of TCF activity through modulating BarHl1 levels 1. Single nuclei will be encapsulated using the 10x Genomics Chromium platform. Two cDNA libraries will be generated: one for 3′ SN RNA sequencing and one for SN ATAC-seq. Sequencing will be performed using short-read, paired-end sequencing, with sufficient depth to detect approximately 3,500–4,000 genes per nucleus. All experimental steps, including sequencing, alignment to the X. laevis v10.1 genome, and quality control, will be carried out by the Curie Institute platform (responsible scientists: Charlene Lasgi and Leanne De Koning).
The bioinformatics part will be done at the IBPS with the PhD student in collaboration with M Doulazmi, IR CNRS (0000-0002-0313-1490) an expert in bioinformatic/biostatistical analysis (CNRS UMR8265, NeuroSU - IBPS - SU). It will benefit from a collaboration with O. Saulnier (0000-0003-4111-1017) a team leader at Curie Institute with expertise in the analysis of large-scale genomic data and in particular the spatial and molecular organization of the human URL. His team is entirely computational and aims at decoding the cellular hierarchies and trajectories of the human hindbrain development to identify and characterize developmental programs hijacked in pediatric brain tumors. We will hire a 2 years bioinformatics engineer (ANR funds) dedicated to the project. The engineer will be on the Institut Curie bioinformatics platform (resp: Nicolas Servant) and benefit from their multi-omics and cross species trajectories expertise. If necessary, the student will receive necessary training for SN-seq and SN(ATAC)-seq transcriptomic analysis through tutoring by the Inforbio platform (IBPS)(resp: Lorette Noiret).

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

CNRS

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