Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification

Author:

Mouilleau Vincent1234,Vaslin Célia123ORCID,Robert Rémi123ORCID,Gribaudo Simona123,Nicolas Nour5ORCID,Jarrige Margot4,Terray Angélique123,Lesueur Léa4,Mathis Mackenzie W.6ORCID,Croft Gist6ORCID,Daynac Mathieu123ORCID,Rouiller-Fabre Virginie5ORCID,Wichterle Hynek6ORCID,Ribes Vanessa7ORCID,Martinat Cécile4ORCID,Nedelec Stéphane123ORCID

Affiliation:

1. Institut du Fer à Moulin, 75005 Paris, France

2. Inserm, UMR-S 1270, 75005 Paris, France

3. Sorbonne Université, Science and Engineering Faculty, 75005 Paris, France

4. I-STEM, UMR 861, Inserm, UEPS, 91100 Corbeil-Essonnes, France

5. Laboratory of Development of the Gonads, Unit of Genetic Stability, Stem Cells and Radiation, UMR 967, INSERM, CEA/DSV/iRCM/SCSR, Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, Université Paris-Saclay, Fontenay aux Roses F-92265, France

6. Departments of Pathology and Cell Biology, Neuroscience, and Neurology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Medical Center, New York, NY 10032, USA

7. Université de Paris, CNRS, Institut Jacques Monod, 15 rue Hélène Brion, 75013 Paris, France

Abstract

ABSTRACT Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether the pace of sequential activation of HOX genes, the 'HOX clock', is controlled by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cell-derived axial progenitors differentiating into diverse spinal cord motor neuron subtypes. We show that the progressive activation of caudal HOX genes is controlled by a dynamic increase in FGF signaling. Blocking the FGF pathway stalled induction of HOX genes, while a precocious increase of FGF, alone or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The pacing of the HOX clock is thus dynamically regulated by exposure to secreted cues. Its manipulation by extrinsic factors provides synchronized access to multiple human neuronal subtypes of distinct rostro-caudal identities for basic and translational applications. This article has an associated ‘The people behind the papers’ interview.

Funder

Association Française contre les Myopathies

Laboratoire d'Excellence (Labex) Biopsy and Revive

Agence Nationale de la Recherche

Fondation pour la Recherche Médicale

Ministre de la Recherche

Project ALS

National Institutes of Health

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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