Project description
How neuronal differentiation in the gut could support regeneration
The function of all nervous systems relies on the concerted activity of diverse neuronal subtypes. In the developing central nervous system (CNS), the axial position of stem cells plays a leading role in determining a cell’s final identity. The enteric nervous system (ENS), which control essential gut functions, is generated from migrating stem cells that lack stable positions. Building on a recent discovery that neuronal diversity in the ENS forms via a step-wise principle and rely on time and identity conversions, the EU-funded divENSify project will reveal the critical epigenetic and transcriptional cues underpinning the generation of ENS neuron subtypes during development and following injury. Subsequent development of regenerative strategies in the adult mouse gut will pave the way for self-repair strategies to treat neurological gut dysfunction.
Objective
The enteric nervous system (ENS) contains a large range of neural subtypes that collectively controls essential gut functions independently of the central nervous system (CNS). Although the ENS is capable of forming new neurons following injury or inflammation, it fails to regenerate completely. My lab recently established a molecular classification of enteric neurons and discovered that they diversify through a conceptually new principle during development. Only two neuronal identities form during neurogenesis while all other classes emerge through subsequent differentiation at the postmitotic stage. This stepwise conversion process contrasts from the better understood CNS development where spatial patterning of stem cells predominates cell fate decisions. Dissecting the molecular basis for the sequential acquisition of cell identities in the ENS will advance our fundamental understanding of cell heterogeneity emergence. In divENSify we propose to push new frontiers in neuronal identity formation to facilitate constructive regeneration in the adult gut. Combining single cell RNA and chromatin profiling we will assess the role of pioneering transcription factors and competent cell states in each step of differentiation. We will dissect gene regulatory networks and identify key determinants using ultrasound-guided gene manipulation, a novel method we recently developed to target the otherwise inaccessible ENS in utero. We will determine how injury-induced adult neurogenesis correlates with developmental paradigms and leverage knowledge on latent potentials and intrinsic transcriptional regulators to engineer specific neuron types through viral gene manipulation in the adult gut. The proposed project will transform our comprehension of neuron identity formation and maintenance and provide proof-of-principle experiments that open for self-repair strategies to treat neurological gut disorders.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
17177 Stockholm
Sweden