Dissecting a stepwise principle of cellular diversification to instruct regeneration in the enteric nervous system

Introduction

The enteric nervous system (ENS) contains a large range of neural subtypes that collectively control 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.

Molecular Classification

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.

Comparison with CNS Development

This stepwise conversion process contrasts with 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.

Project Goals

In divENSify, we propose to push new frontiers in neuronal identity formation to facilitate constructive regeneration in the adult gut. Our specific goals include:

1. Combining single cell RNA and chromatin profiling to assess the role of pioneering transcription factors and competent cell states in each step of differentiation.
2. Dissecting gene regulatory networks and identifying key determinants using ultrasound-guided gene manipulation, a novel method we recently developed to target the otherwise inaccessible ENS in utero.
3. Determining how injury-induced adult neurogenesis correlates with developmental paradigms.

Engineering Neuron Types

We will leverage knowledge on latent potentials and intrinsic transcriptional regulators to engineer specific neuron types through viral gene manipulation in the adult gut.

Conclusion

The proposed project will transform our comprehension of neuron identity formation and maintenance and provide proof-of-principle experiments that open up self-repair strategies to treat neurological gut disorders.