Dr Sumru Bayin
Dr Sumru Bayin
Molecular mechanisms that regulate stem cell behaviours and age-dependent regenerative mechanisms in the brain
Departmental affiliation: Gurdon Institute
Research Summary
An understanding of the diversity of neural progenitors and flexibility in their fate choices - lineage plasticity - is crucial for understanding how complex organs like the brain are generated or undergo repair. The neonatal mouse cerebellum has emerged as a powerful model system to uncover regenerative responses and study progenitor plasticity due to its high regenerative potential. The cerebellum is a folded hindbrain structure that is important for skilled motor movements and higher order cognitive functions. Its protracted development makes the neonatal cerebellum susceptible to injury around birth. Indeed, cerebellar injury and hypoplasia is the second leading risk factor for autism spectrum disorders. Therefore, it is critical to understand the regenerative potential of the neonatal cerebellum and identify factors that could enhance repair.
We have previously shown that the cerebellum can recover from the loss of at least two types of neurons via distinct regenerative mechanisms (Wojcinski, Nature Neuroscience, 2017; Bayin, eLife, 2018; Bayin, Science Advances, 2021). In one case, when the rhombic lip-derived granule cell progenitors are ablated, a subpopulation of the ventricular zone-derived nestin-expressing progenitors (NEPs) that normally generate Bergmann glia and astrocytes undergoes adaptive reprograming and replenishes some of the lost granule cell progenitors. However, the full repertoire of molecular and cellular mechanisms that regulate neonatal cerebellar development and adaptive reprograming of NEPs upon injury remain to be studied.
Interestingly, the regenerative potential of the neonatal cerebellum dramatically decreases once development ends, despite the presence of NEP-like cells in the adult mouse cerebellum. Furthermore, we found they are able to respond to different types of cerebellar injury by increasing their numbers, however neuron production is blocked and only some astrocytes for produced. We hypothesize that the lack of regeneration is due to a lack of pro-regenerative developmental signals in the adult brain in addition to epigenetic silencing of stem cell differentiation programs and inhibitory cellular mechanisms as development is completed.
Our lab is interested in answering two overarching questions:
- What are the cellular and molecular mechanisms that enable regeneration in the neonates and inhibit in the adult?
- Can we facilitate regeneration in the brain?
We aim to undertake the following projects to answer these overarching questions.
Project I: Identify molecular mechanisms that regulate NEP self-renewal, proliferation, differentiation and lineage plasticity during neonatal cerebellar development, and upon injury at birth.
Project II:Characterize stem-like cells in the adult cerebellum and identify the molecular mechanisms that regulate their stemness, and their response to injury.
Project III:Dissect the inhibitory mechanisms for effective regeneration in the adult cerebellum and determine whether activation of developmental programs can facilitate regeneration