PUBLICATION

Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells

Authors
Brunsdon, H., Brombin, A., Peterson, S., Postlethwait, J.H., Patton, E.E.
ID
ZDB-PUB-220430-6
Date
2022
Source
Development (Cambridge, England)   149(10): (Journal)
Registered Authors
Brombin, Alessandro, Patton, E. Elizabeth, Postlethwait, John H.
Keywords
Aldh2, Formaldehyde, Melanocyte stem cell, Metabolism, Purines, Regeneration
Datasets
GEO:GSE178364, GEO:GSE183868
MeSH Terms
  • Stem Cells
  • Melanocytes*
  • Animals
  • Cell Differentiation
  • Neural Crest
  • Zebrafish*
(all 6)
PubMed
35485397 Full text @ Development
Abstract
Melanocyte stem cells (McSCs) in zebrafish serve as an on-demand source of melanocytes during growth and regeneration, but metabolic programs associated with their activation and regenerative processes are not well known. Here, using live imaging coupled with scRNA-sequencing, we discovered that during regeneration quiescent McSCs activate a dormant embryonic neural crest transcriptional program followed by an aldehyde dehydrogenase (Aldh) 2 metabolic switch to generate progeny. Unexpectedly, while ALDH2 is well known for its aldehyde clearing mechanisms, we find that in regenerating McSCs Aldh2 activity is required to generate formate - the one-carbon (1C) building block for nucleotide biosynthesis - through formaldehyde metabolism. Consequently, we find that disrupting the 1C cycle with low doses of methotrexate causes melanocyte regeneration defects. In the absence of Aldh2, we find that purines are the metabolic end product sufficient for activated McSCs to generate progeny. Together, our work reveals McSCs undergo a two-step cell state transition during regeneration, and that the reaction products of Aldh2 enzymes have tissue-specific stem cell functions that meet metabolic demands in regeneration.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b1266
    		Deficiency
    cz3335TgTransgenic Insertion
      ue406
        		Small Deletion
        vc7
          		Point Mutation
          w47TgTransgenic Insertion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            adh5CRISPR1-adh5CRISPR
            aldh2.1CRISPR1-aldh2.1,aldh2.2CRISPR
            aldh2.1MO1-aldh2.1MRPHLNO
            aldh2.2CRISPR1-aldh2.1,aldh2.2CRISPR
            aldh2.2MO1-aldh2.2MRPHLNO
            1 - 5 of 5
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            Fish
            No data available
            Antibodies
            Name Type Antigen Genes Isotypes Host Organism
            Ab3-aldh2polyclonal
              		IgGRabbit
              1 - 1 of 1
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              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              GFPEFGGFP
              mCherryEFGmCherry
              1 - 2 of 2
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              Mapping
              No data available
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              Citation
              Brunsdon, H., Brombin, A., Peterson, S., Postlethwait, J.H., Patton, E.E. (2022) Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells. Development (Cambridge, England). 149(10):.