Resolving cell lineages and gene functions in the developing mouse gastrointestinal tract using in utero transduction.

Authors

Ziwei Liu, Krishnanand Padmanabhan, Jingyan He, Katrin Hector, Bettina Semsch, Jia Sun, Viktoria Knoflach, Sarantis Giatrellis, Johan Lorentz, Khachatur Dallakyan, Christian Göritz, Emma Rachel Andersson, Ulrika Marklund

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 37. Pages e2614077123. Sep 15, 2026. Epub Sep 09, 2026.

Abstract

How diverse cell lineages emerge and are genetically regulated during organogenesis are central questions in understanding the developmental origins of disease. However, the mouse gut, including its intrinsic enteric nervous system (ENS) derived from migratory neural crest, has remained difficult to experimentally target. Here, we introduce an in utero lentiviral nano-injection strategy that enables early and efficient access to progenitor cells of all major cell types within the developing gut as well as gut-innervating ganglia. Leveraging this approach in combination with DNA barcoding and single-cell transcriptomics, we resolve clonal relationships in all gut lineages, including epithelial, neural, immune, and mesenchymal cell types. Clonal coupling between distinct subsets of fibroblasts and either pericytes, mesothelial cells, or interstitial cells of Cajal, suggested a developmental logic whereby the mesenchymal compartment arises from a set of fate-biased progenitors. Yet, mesenchymal regionalization along the anterior-posterior axis establishes early, whereas the ENS displays broad clonal dispersion across gut regions and acquires subsequent regional identities. We further adapted the platform for temporally controlled cell-type specific gene manipulation and, as a proof-of-principle, show that induced expression of the proneural factor Ascl1 biases ENS progenitor cells toward neuronal differentiation. Together, this work provides insights into refined spatiotemporal lineage relationships within a multigerm-layer organ and establishes a broadly applicable in vivo framework for probing gene function during gastrointestinal and neural crest development.

PMID:
42715084
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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