Project ID NS-MH2024_65


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Centre for Developmental NeurobiologyWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Centre for Developmental NeurobiologyWebsite

Synaptotropic, dendrite-first Purkinje cell migration – a new locus for Autistic Spectrum Disorder?

The formation of synaptic connections in the central nervous system relies on particular subsets of proteins that are also implicated in cognitive disorders such as Autistic Spectrum Disorder (ASD). While the formation of wiring is hence a key suspect in ASD, we hypothesise that earlier events, which involve the migration of newborn brain cells using temporary synaptic scaffolds to claw their way into position, are equally significant. Evidence for this hypothesis comes from the Purkinje cell of the cerebellum and the transient formation of focal synaptic cell adhesion molecules in emerging neurites at sites that do not ultimately become synpases. While this is one of the most studied cells in the brain, with a clear part to play in the genesis of ASD, remarkably little is known about its development. A combination of preliminary evidence and a scattering of historical studies suggest that Purkinje cells use their juvenile dendrites to feel their way into position, forming transient synapses as they do so. The thesis will characterise this ‘synaptotropic migration’ and explore how it is regulated by pre and postsynaptic ASD target genes.

This project will
1. Characterise Purkinje cell migration in the developing chick cerebellum using electroporation of GFP, fluorescently labelled synaptic proteins
2. Use electroporation of pre-cerebellar nuclei to establish the transient synaptic partners of Purkinje cell dendrites
3. Undertake time-lapse analysis of synaptic proteins, dendritic remodelling to understand the molecular basis of a “biased choice” model of synaptotropic migration
4. Assess the consequences of disrupting ASD targets genes and synaptic protein formation specifically in Purkinje cells using electroporation of CRISPR-Cas9 constructs

Year 1: Establishing techniques of Purkinje cell and pre-cerebellar axon labelling and initial characterisation of migration. Surveying candidate proteins and designing CRISPR-Cas9 targets
Year 2: Assessing migration by time-lapse in cerebellar slices in culture. Disruption of proteins involved in ASD and synapse formation using CRISPR
Year 3: Analysis of interactions between Purkinje cells and pre-cerebellar axon scaffolds using autonomous and cell non-autonomous disruption of pre- and post-synaptic proteins

Representative Publications

Sox14 Is Required for a Specific Subset of Cerebello-Olivary Pojections. Prekop HT, Kroiss A, Rook V, Zagoraiou L, Jessell TM, Fernandes C, Delogu A, Wingate RJT (2018) J Neurosci DOI: 10.1523/JNEUROSCI.1456-18.2018.

Conserved and divergent development of brainstem vestibular and auditory nuclei. eLife Lipovsek M, Wingate RJ (2018). DOI: 10.7554/eLife.40232.

Mitotic granule cell precursors undergo highly dynamic morphological transitions throughout the external germinal layer of the chick cerebellum. Hanzel M, Rook V, Wingate RJT (2019) Scientific reports DOI:

‘An ESCRT module is required for neuron pruning. Nicolas Loncle, Monica Agromayor, Juan Martin-Serrano & Darren W. Williams (2015) Scientific Reports DOI

Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity. eLife William D Constance, Amrita Mukherjee, Yvette E Fisher, Sinziana Pop, Eric Blanc, Yusuke Toyama, Darren W Williams (2018) eLife DOI:

Extensive and diverse patterns of cell death sculpt neural networks in insects. Sinziana Pop, Chin-Lin Chen, Connor J Sproston, Shu Kondo, Pavan Ramdya, Darren W Williams (2020) DOI: