The Testa Group harnesses the unprecedented potential of cell reprogramming to study the molecular basis of human neuropsychiatric and neurological diseases (NPD), by chasing the dynamics of their unfolding in physio pathologically relevant models and straddling multiple scales of analysis from single cell resolution to organismal function.
One of the most tangible outputs of somatic cell reprogramming has been a paradigm shift in our ability to model human diseases, for which fundamental limitations have been so far: i) the scarce availability of primary diseased tissues, which is particularly salient for disorders of the nervous system; and ii) the difficulty of reconstructing developmental and patient-specific trajectories during the unfolding of diseases.
We are thus pursuing NPD modelling with human induced pluripotent stem cells (iPSC) coupled with the differentiation into relevant lineages through a range of complementary experimental paradigms, including glutamatergic neurons by induced expression of neurogenin-2 (NGN2), neural crest stem cells and 3-dimensional brain organoids that recapitulate salient stages of early brain development, including the diversity of cell populations unique to the human brain. This is allowing us to dissect the genetic and environmental components of NPD pathogenesis, by means of several “omics” approaches at a bulk and single cell resolution integrated with high throughput imaging and functional in vitro and in vivo assays.
The Testa Group focuses on a uniquely informative range of syndromes featuring intellectual disability and autism spectrum disorder that are caused by mutations or dosage alterations in epigenetic regulators and transcription factors, including Williams-Beuren Syndrome and 7q11.23 microduplication Syndrome, Kabuki Syndrome, ADNP-related autistic spectrum disorders, Weaver Syndrome, Gabriele-Testa-DeVries Syndrome, as well as on paradigmatic environmental factors that adversely impact on neurodevelopment, namely endocrine disruptive chemicals.
Finally, the prism of human neurodevelopmental disorders is also allowing us to investigate the logic of the gene regulatory networks underlying the evolution of the modern human face and brain, integrating the analysis of craniofacial dysmorphologies and brain alterations to illuminate the evolutionary-developmental trajectories underlying the modern human condition.
Head of Neurogenomics Research Centre
Alejandro Lopez Tobon
- 09/2020 - Molecular Autism
Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology
The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to […]
- 09/2020 - Nature
LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of […]
- 06/2020 - Molecular Autism
Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; […]
- 06/2020 - Neurosci Insights
KMT2B and Neuronal Transdifferentiation: Bridging Basic Chromatin Mechanisms to Disease Actionability
The role of bona fide epigenetic regulators in the process of neuronal transdifferentiation was until recently largely uncharacterized, despite their key role in the physiological processes of neural fate acquisition and maintenance. In this commentary, we describe the main findings of our recent paper “KMT2B is selectively required for neuronal transdifferentiation, and its loss exposes dystonia candidate […]