Overview
Humans display an exceptionally complex brain compared to other species, both in neuron number and cellular complexity, enabling advanced cognitive abilities;
however, how human-specific neural features emerge remains largely unclear. This question is particularly striking in the cerebellum, a brain region that contains ~80% of all neurons and plays a key role in the evolution of complex traits such as tool use and language. Among cerebellar cell types, Purkinje neurons are central to these processes and represent the largest and most morphologically complex neurons in the human brain, displaying a disproportionate expansion of dendritic architecture compared to other species and brain regions. Using novel cerebellar organoid models cultured at the air-liquid interface, combined with integrative omics and quantitative morphometrics, we aim to dissect the mechanisms that drive region- and species-specific neuronal morphogenesis, with a particular focus on the extreme growth of human Purkinje neurons. Notably, these neurons are highly vulnerable and selectively degenerate in many paediatric eurodevelopmental disorders, phenotypes that cannot be faithfully recapitulated in animal models. We will therefore test whether human-specific cellular features underlie this heightened sensitivity, with the dual goal of uncovering disease mechanisms and developing gene-therapy-based strategies to reverse degeneration and improve clinical outcomes.
Research directions
- Dissecting human-specific mechanisms linking divergent genomic states to neuronal morphogenesis
The human brain contains hundreds of neuronal and glial cell types, each defined by distinct genomic and epigenomic configurations that shape cell morphology, connectivity, and function. Neurons that share broad classes, such as excitatory and inhibitory cortical neurons, differ strikingly from neurons generated in other brain regions, including cerebellar lineages, suggesting that developmental origin establishes region-specific “genomic states” that constrain and enable specific morphogenetic programs. We investigate how developmental origin and lineage history specify these genomic states, and how they are translated into neuronal morphogenesis and circuit-relevant properties in humans. A central motivation is that many germline mutations produce region-selective vulnerability: some neuronal populations degenerate or malfunction, while others remain relatively protected. By integrating human stem-cell–derived models with quantitative morphometrics and multi-omic profiling, we aim to identify the regulatory programs that couple identity to form, and to define why certain neuron types are preferentially susceptible to disease. - Accelerating therapeutic approaches for genetic cerebellar disorders
The cerebellum-particularly Purkinje cells-is highly vulnerable to both monogenic and multigenic disorders. In conditions such as ataxia-telangiectasia, spinocerebellar ataxias, and ARSACS, progressive cerebellar degeneration leads to ataxia and severe motor impairment; in other cases, disrupted development causes cerebellar hypoplasia and lifelong disability. Despite strong genetic causality, therapeutic development is limited by the lack of human-relevant experimental systems that capture cerebellar cytoarchitecture, maturation, and clinically meaningful windows for intervention. Using innovative human cerebellar models grown at the air-liquid interface, we are building a platform to (i) model disease mechanisms in a tissue context, and (ii) evaluate gene-therapy strategies in a way that is difficult to achieve in conventional cultures. These models enable controlled testing of therapeutic timing, dosing, and delivery modalities while monitoring cell-type-specific outcomes, including Purkinje cell integrity and circuit-relevant maturation. Our goal is to establish a hub for mechanism-to-therapy translation for rare genetic cerebellar disorders.
Group members
Luca Guglielmi PI
We are currently hiring for a post-doctoral role in studying genetics of cerebellar disorders using Air-liquid-interface cerebellar organoids We are constantly looking for skilled people at both undergraduate student to
postdoc level. Substantial help for research and raising funds (fellowships etc.) is available
Please contact directly the PI Luca Guglielmi (luca.guglielmi-1@unitn.it)
Collaborations
Madeline Lancaster, MRC Laboratory of Molecular Biology, Cambridge, UK
Yi-Chun Tung, Institute of Metabolic Science, Cambridge, UK
Gabriel Balmus, UK Dementia Research Institute, Cambridge, UK
Matthias Carl, CIBIO, Trento, Italy
Lucia Poggi, CIBIO, Trento, Italy
Chiara Magliaro, Centro di Ricerca E. Piaggio, Pisa, Italy
Fundings
Fondazione Telethon Cariplo 2025 grant Title: Modeling and Targeting LRCH2-Associated Cerebellar Hypoplasia Using AirLiquid-Interface Human Cerebellar
Organoids and Zebrafish Embryos (Coordinator)
Selected publications
Below 7 selected publications out of 21
# Corresponding author
* Equal contribution
Georgina Miller, Daniel Lloyd-Davies Sanchez, José González Martínez, Alexander W. Justin, Madeline A. Lancaster# & Luca Guglielmi #. Organizers in a
Dish: Modeling Human CNS Morphogenesis. Accepted in Developmental Cell.
Guglielmi, L#., Lloyd-Davies-Sánchez, D., González Martínez, J. & Lancaster, M. A#. A minimally guided organoid model for cross-species comparisons of cerebellar development. bioRxiv 2024.10.02.616236 (2024) doi:10.1101/2024.10.02.616236.
Wilcockson SG., Guglielmi L., Araguas Rodriguez P., Amoyel M., Hill CS. An improved Erk biosensor detects oscillatory Erk dynamics driven by mitotic erasure
during early development. Dev Cell. 2023 Sep 9:S1534-5807(23)00436-7. doi: 10.1016/j.devcel.2023.08.021.PMID: 37714159
Richardson L., Wilcockson SG., Guglielmi L., Hill CS. Context-dependent TGFβ family signalling in cell fate regulation. Nat Rev Mol Cell Biol. 2023 Aug 18. doi:
10.1038/s41580-023-00638-3. PMID: 37596501
Economou, A. D*., Guglielmi, L*., East, P. & Hill, C. S. Nodal signaling establishes a competency window for stochastic cell fate switching. Dev Cell. 2022 Dec
5;57(23):2604-2622.e5. doi: 10.1016/j.devcel.2022.11.008.PMID: 36473458.
Servettini I., Talani G., Megaro A., Setzu MD., Biggio F., Briffa M., Guglielmi L., Savalli N., Binda F., Delicata F et al. An activator of voltage-gated K+ channels Kv1.1
as a therapeutic candidate for episodic ataxia type 1. Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2207978120. doi: 10.1073/pnas.2207978120. Epub 2023. Jul
24. PMID: 37487086
Guglielmi, L., Heliot, C., Kumar, S., Alexandrov, Y., Gori, I., Papaleonidopoulou, F., Barrington, C., East, P., Economou, A.D., French, P.M.W., McGinty, J., Hill, C.S.
Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways (2021). Nature Communications, 12
(1), art. no. 6374. DOI: 10.1038/s41467-021-26486-3. PMID: 34737283.