Project ID NS-MH2023_50


Co Supervisor 1A IoPPN/Centre for Developmental NeurobiologyWebsite

Co Supervisor 1B IoPPN/Centre for Developmental NeurobiologyWebsite

Deciphering the molecular mechanisms of macrocephaly in Malan syndrome

Malan syndrome is a rare genetic overgrowth disorder, which is clinically characterized by unusual facial features and macrocephaly associated with intellectual disability. Whilst Nfix transcription factor has been identified as a causal gene of the syndrome, the molecular mechanisms underlying the syndrome causality remain obscure.

Our proposal aims to identify the developmental causative mechanisms of Malan syndrome macrocephaly by focusing on Nfix isoform expression and function to decipher the influence of the disease mutations on their genome-wide transcriptional activity. To this end, we will employ three complementary experimental approaches; mouse ES cell-based cortical differentiation that allows us to investigate the various mutations, in vivo mouse manipulation to validate the expected findings of in vitro systems, and human 3D organoids to evaluate the impact of disease mutations in the context of human brain development.

The student will learn various latest molecular, cellular and anatomical techniques including ES cell-based neuronal differentiation and gene editing. These activities will be supported by supervisors (Dr Sahara: mouse ES cells and in vivo mouse analysis, Prof Hindges (Academic Director of Genome Editing Core): CRISPR gene editing, as well as onsite collaborators (Prof Berninger: human brain organoids, Prof Makeyev: Bioinformatics).

Work Plan:
Year1 (Or Lab rotation):
Investigating Nfix isoform function in mouse ES cell-based cortical differentiation
Functional and transcriptome analysis of mouse cortical progenitors carrying Nfix mutations
In vivo evaluation of Nfix mutant in vivo mouse embryonic cortex
Year3-4: Functional and transcriptome analysis of human organoids cortical progenitors carrying Nfix mutations

Representative Publications

Ramos, S.I., Makeyev, E.V., Salierno, M., Kodama, T., Kawakami, Y., and Sahara, S. (2020). Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini. Developmental Cell 52, 477-491.e8.

Antinucci, P., Suleyman, O., Monfries, C., and Hindges, R. (2016). Neural Mechanisms Generating Orientation Selectivity in the Retina. Current Biology 26, 1802–1815.