Project ID NS-MH2023_36

ThemeNS-MH

Co Supervisor 1A IoPPN/Centre for Developmental NeurobiologyWebsite

Co Supervisor 1B IoPPN/Centre for Developmental NeurobiologyWebsite

Understanding neuronal migration disorders using human tissue models

The cerebral cortex is the seat of many of the higher cognitive functions that make us human, such as our advanced learning and speech. We know that the correct organisation of the cortex is vital for these functions, but how this is achieved during development remains elusive. Evidence from studies on neurodevelopmental disorders has indicated that neuronal migration is crucial to ensure that the right number of neurons end up in the right place at the right time. A key example of such a disorder is lissencephaly, where the folding of the cortex (the wrinkles on the outer surface) is greatly reduced. This lack of folding is associated with cognitive defects and has been suggested to be due to an over-migration of neurons.

This project will use cutting-edge human cell and tissue culture systems to investigate how neuronal migration is dysregulated in neurodevelopmental disorders. It will take advantage of both laboratories’ expertise, combining the Long lab’s experience in human fetal neocortex development and explant models with the Berninger lab’s experience in human induced pluripotent stem cells (iPSC) and organoid models. We will use a multidisciplinary approach, including live-imaging, transcriptome analysis, confocal-imaging and cell biology.

The student will investigate:
Year 1 – Neuronal migration in human fetal neocortex explant models of lissencephaly; establishment of human cerebral organoids from iPSCs
Year 2 – Neuronal migration in iPSC/organoid models and effect of tissue/substrate stiffness
Year 3 – Identification of mechanisms underlying defects in neuronal migration; rescue of these defects in iPSC/organoid and human fetal neocortex models

One representative publication from each co-supervisor:

Long KR, Newland B, Florio M, et al. Extracellular Matrix Components HAPLN1, Lumican, and Collagen I Cause Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex. Neuron. July 2018. doi:10.1016/j.neuron.2018.07.013

Karow M, Camp JG, Falk S, et al., Berninger B. Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program. Nat Neurosci. July 2018. doi: 10.1038/s41593-018-0168-3.