Peter Swoboda

Cilia in the brain – and their connections to human brain disorders


Cilia are sensory or signalling structures projecting off cell surfaces like an antenna. In humans, many different cell types are ciliated, including neurons in the brain. Neuronal cilia as signalling hubs are involved in shaping and maintaining functional neuronal circuits. These circuits are crucial for orchestrating behavioural output. Ciliopathies are characterised by defective cilia and comprise various disease states, including brain phenotypes.

We have uncovered highly relevant connections between (i) cilia, ciliary genes and cilia-based signalling and (ii) (candidate genes for) different human brain conditions or disorders, like dyslexia or schizophrenia. The biological pathways behind these brain phenotypes are largely unknown. And our understanding of neuronal cilia is still rudimentary.

Fundamental questions about ciliary involvement in brain development, function and behavioural output in normal and disease states remain. What are the mechanisms by which cilia orchestrate cellular signalling in neuronal development? When and how does ciliary signalling control cell fate during expansion of the neural progenitor cell pool and their differentiation and organisation into neurons during brain development? Addressing these questions is crucial for understanding disease aetiology and for eventually developing treatment regimens for brain disorders.

graph and photo
Behavioural output: In the head of the worm C. elegans two bilaterally symmetrical salt-tasting neurons are marked with GFP. The neuron at the top has a fully functional sensory cilium (arrowhead) and thus is able to “taste” salt (see calcium imaging trace on the left). The neuron at the bottom is defective for cilium development and thus cannot “taste” salt (see calcium imaging trace on the left). Photo: Swoboda group

Our work lets us hypothesise that proper cilia function impacts differentiation of neural progenitor cells and early-stage neurons, including polarisation and neurite outgrowth, and thereby neuronal migration and circuit formation later on. Different non-lethal cilia malfunctions may thus cause different brain phenotypes (or disease states) depending on the affected neuron type and its location in the brain.

We address these hypotheses by:

  • Determining in cultured human neurons and a whole-animal model, the worm C. elegans, causative connections between cilia formation, structure and function and aspects of neuronal development.
  • Analysing transcriptomes of differentiating (human) neurons, including bioinformatics-based cross-correlations with ciliary gene lists and human candidate genes for various brain phenotypes.
  • Analysing in the worm C. elegans behavioural output of disease-associated mutations in evolutionarily conserved (human and worm) ciliary genes connected to brain phenotypes.

Our goal is to create proper spatiotemporal information about ciliary localisation and function of proteins encoded by disease genes to better understand human brain development in the context of neural progenitor cells, and differentiating and mature functional neurons.

Group members

Peter Swoboda

Group leader

Mariangela Pucci

Affiliated to research

Selected publications

  1. Lauter G, Swoboda P, Tapia-Páez I. (2018), ’Cilia in brain development and disease.’ Cilia: Development and Disease. 2018 May 31 (ed. P. Goggolidou, CRC Press, Taylor and Francis Publishers, Boca Raton, Florida, USA); ch. 1:pp. 1-35.
     
  2. Sugiaman-Trapman D, Vitezic M, Jouhilahti EM, Mathelier A, Lauter G, Misra S, Daub CO, Kere J, Swoboda P. (2018) ‘Characterization of the human RFX transcription factor family by regulatory and target gene analysis.’ BMC Genomics. 2018 Mar 6;19:181.
     
  3. Tammimies K, Bieder A, Lauter G, Sugiaman-Trapman D, Torchet R, Hokkanen ME, Burghoorn J, Castrén E, Kere J, Tapia-Páez I, Swoboda P. (2016) ‘Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs.’ FASEB J. 2016 Oct;30(10):3578-3587.
     
  4. Ezcurra M, Walker DS, Beets I, Swoboda P, Schafer WR. (2016), ‘Neuropeptidergic signaling and active feeding state inhibit nociception in Caenorhabditis elegans.’ J Neurosci. 2016 Mar 16;36(11):3157–3169.

Research networks

  • KI Neurosciences network
  • European C. elegans researcher network (EU COST Action Network BM1408)
  • Swedish-Korean research cooperation network (VR and STINT, Korean NRF)