Development and Function of the Enteric Nervous System

The Marklund lab focuses on cell diversity in the Enteric Nervous System. By determining the variety of ENS cell subtypes, the functions they normally serve and their developmental specification we aim to improve diagnostic and therapeutic principles for gut disorders. The lab addresses these basic but critical questions by transcriptome analysis coupled with viral-based activity/gene manipulations primarily using the mouse model.

Unique amongst visceral organs, the gastrointestinal tract contains an own intrinsic nervous system. This so-called enteric nervous system (ENS) is the largest and most complex part of the peripheral nervous system and provides the gut autonomous control of peristalsis, blood flow and secretion. An even broader functional significance of the ENS is being recognised through its communication with the brain, immune system and microbiota. ENS dysfunction has been associated with many disorders including Hirschsprung disease, achalasia and Parkinson's disease. Despite the essential role of ENS in gut physiology and disease, the variety of functionally distinct neurons and how they specify during development has not been resolved. By applying single cell transcriptome analysis we have recently established a new classification of enteric neuron subtypes and a mechanistic mode for how these neuron identities emerge. The molecular definition of enteric neuron classes give us a foundation to reveal their detailed developmental programs and precise functions both within and outside the gut.

KEY FINDINGS 

STEP-WISE DIVERSIFICATION

ENTERIC NEURON CLASSES

Illustrator: Mattias Karlén

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1. DEVELOPMENT OF CELL DIVERSITY IN THE ENTERIC NERVOUS SYSTEM

We have revealed a novel principle underlying neuronal diversification in the developing ENS (Morarach et a., 2021). Unlike the (better understood) developing central nervous system, where cardinal identities already are instructed within dividing progenitor cells of the neural tube, cellular identities in the ENS are formed through a prolonged step-wise process. ENS stem cells undergoing neurogenesis only undertake one out of two "prototypic" identities and then continue to diversify at the post-mitotic stage (see depiction above). Future projects aim to determine molecular mechanisms that allow neurons to switch identities and the distinct developmental programs for each enteric neuron class. We hope (and believe) that our insights will provide the necessary information to design regenerative medicine for gut disorders and new conceptual thinking around neural cell fate formation and maintenance. 

Read more about the background in:

2: FUNCTION OF ENTERIC NEURON CLASSES

We have presented a molecular definition of enteric neuron and glial classes of the murine small intestine (Morarach et al., 2021; Zeisel et al., 2018). The molecular profiles allowed us to predict their physiological roles in classic ENS-mediated processes (such as peristalsis), but also in more unexplored territories such as in immunoregulation. In current and future projects we use viral-mediated targeting of specific classes in transgenic mice to reveal the intricate cellular connectomes of the ENS in the gut wall - as well as outside. By dissecting the cellular units and their interactions we hope to provide a foundation to better understand gut disorders with unclear etiologies and identify new targets for novel therapeutic measures.

Read more about the background in:

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We are grateful for the generous FUNDING from:

Current Funding:
  • ERC CoA
  • Knut & Alice Wallenberg Foundation
  • Karolinska Institutet Foundations
  • SFO StratNeuro
  • NIH
  • Swedish Research Council CoA
  • Hjärnfonden (Brain Foundation)
  • Ollie and Elof Ericssons Foundation
Lab members stipend:
China Scholarship Council
KID
Wenner-Gren Foundation
Past Funding:
  • Svenska Läkaresällskapet (Swedish Medical Society)
  • SFO StratRegen
  • Ruth & Richard Julin Foundation
  • Magnus Bergvall Foundation
  • Åke Wiberg Foundation
  • Li Dak Sum Foundation
  • Eva & Oscar Ahren Foundation
Lab members stipend:
SSMF
Wenner-Gren Foundation
Hjärnfonden
Royal Thai Government