Leukocyte Tyrosine Kinase Functions in Pigment Cell Development
Open accessAbstract
A fundamental problem in developmental biology concerns how multipotent precursors choose specific fates. Neural crest cells (NCCs) are multipotent, yet the mechanisms driving specific fate choices remain incompletely understood. Sox10 is required for specification of neural cells and melanocytes from NCCs. Like sox10 mutants, zebrafish shady mutants lack iridophores; we have proposed that sox10 and shady are required for iridophore specification from NCCs. We show using diverse approaches that shady encodes zebrafish leukocyte tyrosine kinase (Ltk). Cell transplantation studies show that Ltk acts cell-autonomously within the iridophore lineage. Consistent with this, ltk is expressed in a subset of NCCs, before becoming restricted to the iridophore lineage. Marker analysis reveals a primary defect in iridophore specification in ltk mutants. We saw no evidence for a fate-shift of neural crest cells into other pigment cell fates and some NCCs were subsequently lost by apoptosis. These features are also characteristic of the neural crest cell phenotype in sox10 mutants, leading us to examine iridophores in sox10 mutants. As expected, sox10 mutants largely lacked iridophore markers at late stages. In addition, sox10 mutants unexpectedly showed more ltk-expressing cells than wild-type siblings. These cells remained in a premigratory position and expressed sox10 but not the earliest neural crest markers and may represent multipotent, but partially-restricted, progenitors. In summary, we have discovered a novel signalling pathway in NCC development and demonstrate fate specification of iridophores as the first identified role for Ltk.
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In silico inhibition of Ltk signalling in models A1 and A2 failed to predict the experimentally observed initial activation followed by downregulation of ltk, tfec and pnp4a expression as iridoblasts differentiate into iridophores.
“Finally, in silico inhibition of Ltk signalling in models A1 and A2 failed to predict the experimentally observed initial activation, followed by downregulation, of ltk [9], tfec (Fig 3C) and pnp4a (S1C–S1F Fig) expression as iridoblasts differentiate into iridophores.”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
The citation to this paper is attached to ltk expression, not to the model results or the claims about tfec and pnp4a. Although the paper reports early ltk expression, its Discussion (Figure 8; page unavailable) says specified iridoblasts maintain ltk expression as they differentiate into iridophores, contrary to the attributed downregulation. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredLtk signalling is crucial to fate specification, proliferation and differentiation of iridophores.
“a signalling pathway crucial to fate specification, proliferation and differentiation of iridophores has been highlighted by mutations in the gene encoding the Leukocyte Tyrosine Kinase (Ltk; [11, 36]) receptor tyrosine kinase”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
The Discussion states that Ltk is crucial for iridophore fate specification in zebrafish. It proposes proliferation as a likely late function but says the early mutant phenotype prevents direct examination of Ltk’s role in differentiating cells. The Results report no significant effect on neural crest cell proliferation, so the claim overstates the evidence for proliferation and differentiation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn shady/ltk mutants, fate specification and proliferation of iridophores, but not other pigment cells, are impeded.
“In shady/ltk mutants fate specification and proliferation of iridophores, but not other pigment cells, are impeded [11, 36].”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
The Results sections on iridophore markers and the shd allelic series support impaired iridophore fate specification, with melanophores and xanthophores generally comparable to wild-type siblings. But the Results section on iridophore markers says a primary role in iridoblast proliferation was unlikely and reports no significant effect on neural crest cell proliferation. Thus, the attributed proliferation defect is not supported. (LLM, conf=0.91)
Experimental — accuracy not yet measuredAt approximately 22 hpf, ltk and mitfa are upregulated in the tfec+; foxd3- premigratory cells of the trunk, indicating they correspond to partially restricted progenitors capable of generating pigment cells.
“At approximately 22 hpf, ltk and mitfa are upregulated in the tfec+; foxd3- premigratory cells of the trunk [11, 14, 21], indicating that they correspond to partially restricted progenitors, capable of generating pigment cells”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
The Results report ltk expression in premigratory trunk neural crest cells and place it after expression of foxd3; the Discussion describes foxd3-negative, ltk-expressing cells in sox10 mutants as possible partially restricted progenitors. The Discussion also places the onset of mitfa expression in the posterior trunk at approximately 21 hpf. The paper does not establish that ltk and mitfa are upregulated together at approximately 22 hpf in tfec-positive, foxd3-negative cells, or demonstrate the developmental potential of that specific cell population. No page numbers were supplied for these sections. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThese cells co-express ltk, suggesting they correspond to specified iridoblasts.
“These cells co-express the definitive lineage marker, ltk [11, 14], suggesting that they correspond to specified iridoblasts.”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
The Results section interprets strongly ltk-expressing cells as iridoblasts and suggests that ltk marks the iridophore lineage. But the Discussion (Figure 8) proposes that early ltk expression also occurs in partially restricted, multipotent neural crest cells. Thus ltk expression supports the suggested identity, but this paper does not establish it as a definitive marker of specified iridoblasts. (LLM, conf=0.87)
Experimental — accuracy not yet measured
In sox10 mutants, NC derivatives fail to become specified and to enter the migration pathways.
“Specifically, as was previously reported for a single time point [14], in sox10 mutants, where NC derivatives fail to become specified and to enter the migration pathways [11, 20], tfec expression is maintained in trapped late Cbls, extending to the hindbrain/trunk boundary (Fig 7A and 7B).”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
The Results section (page unavailable) describes a general failure of fate specification in non-ectomesenchymal neural-crest derivatives and reports that a large proportion of neural-crest cells in sox10 mutants fail to migrate. The claim omits those limits: the paper does not say that all neural-crest derivatives fail to specify or enter migration pathways, and it notes occasional differentiated escapees. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn tfec mutants, the ability to express the lineage markers of melanocytes and xanthophores is delayed but otherwise unaffected, whereas ltk expression is completely missing, even in premigratory cells, contrasting the phenotype of sox10 mutants.
“We show here that in tfec mutants the ability to express the lineage markers of melanocytes and xanthophores is delayed but otherwise unaffected, whereas ltk expression is completely missing, even in premigratory cells, also contrasting the phenotype of sox10 mutants [11].”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredNeither transitional cells nor ML expressed genes for Tfec or Ltk.
“neither transitional cells nor ML expressed genes for Tfec, a transcription factor essential for iridophore specification (21) or Ltk, a receptor tyrosine kinase essential for iridophore differentiation and morphogenesis (22)”
From Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish (2025) · cites this paper as [22]
Citation (22) is attached to the description of Ltk, not to the citing authors’ observation that transitional cells and ML lack Ltk expression. The Discussion (page unavailable) identifies Ltk as a receptor tyrosine kinase crucial for iridophore specification, but says the early mutant phenotype prevents direct examination of its role in differentiating cells. Our copy does not establish that Ltk is essential for iridophore differentiation or morphogenesis specifically. (LLM, conf=0.88)
Experimental — accuracy not yet measuredConstitutively activated Ltk signalling drives neural crest cells to adopt an iridophore fate.
“constitutively activated Ltk signalling driving NCCs to adopt an iridophore fate [9], [27], [28].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
The Discussion (Figure 8; page unavailable) proposes that Ltk signalling, together with Sox10, initiates iridoblast specification from neural crest cells. The paper supports a role for Ltk in that fate choice, but the passages do not show that constitutively activated Ltk signalling drives it. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLoss-of-function ltk mutants lack embryonic and adult iridophores.
“with loss of function mutants lacking embryonic and adult iridophores”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
The Results section, “Shd mutants have reduced iridophores and form a broad allelic series” (page not provided), reports that strong mutants have very few embryonic iridophores. It does not support the claim that mutants lack adult iridophores: adult-viable alleles have reduced iridophores or are phenotypically normal. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPremigratory NCCs in the trunk and tail go through a multipotent pigment cell progenitor phase, referred to as the Cbl phase.
“led us to propose that premigratory NCCs in the trunk and tail go through a multipotent pigment cell progenitor phase, that we refer to here as the Cbl phase (Fig 7).”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
The Results section (‘shd expression is prominent in NCCs and iridophores’; page unavailable) places early ltk expression in a subset of premigratory NCCs in the trunk and tail. The Discussion (Figure 8; page unavailable) proposes that these cells may be partially restricted, multipotent pigment-cell progenitors. The source does not establish that premigratory NCCs generally pass through this phase; ‘Cbl phase’ is the citing authors’ own name for it. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAt 18 hpf, neither mitfa nor ltk and pnp4a are detectable by WISH in tfec-positive neural crest cells of the trunk.
“At this stage neither the melanoblast marker mitfa nor two other early iridoblast markers ltk and pnp4a were detectable by WISH in tfec-positive NCCs of the trunk (Fig 1B) [9], [44].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
The Discussion (page unavailable) places the onset of mitfa expression in the posterior trunk at approximately 21 hpf, consistent with its absence there at 18 hpf. But the Results report ltk expression in a subset of premigratory trunk neural crest cells beginning between 18 and 28 hpf. The paper does not establish whether those cells are tfec-positive or address pnp4a detection in them, so it does not support the full claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSeveral requirements for iridophore development from the neural crest are known.
“Several requirements for iridophore development from the neural crest are known [5], [26], [27].”
ltk is highly enriched in iridophores compared to melanocytes.
“For instance, ltk, known to be a marker of iridophores, is highly enriched in iridophores compared to melanocytes (red square with x in Figure S4) [27].”
ltk is required for iridophore development.
“We found a single receptor tyrosine kinase enriched in iridophores, ltk, which we have previously shown to be required for iridophore development [27].”
ltk is the single receptor tyrosine kinase enriched in iridophores.
“We found a single receptor tyrosine kinase enriched in iridophores, ltk, which we have previously shown to be required for iridophore development [27].”
The iridophore enrichment list includes factors known to be important for iridophore development, including ltk, ednrb1, and pnp4a.
“Included in this enrichment list are several factors known to be important for iridophore development, including ltk, ednrb1, and pnp4a [5], [26], [27].”
ltk, ednrb1, and pnp4a are known to be important for iridophore development.
“Included in this enrichment list are several factors known to be important for iridophore development, including ltk, ednrb1, and pnp4a [5], [26], [27].”
Ltk signalling alone is not sufficient for iridophore specification.
“Nevertheless, Ltk signalling alone is not sufficient for iridophore specification, since iridophores are eliminated in sox10 mutants, even though ltk expression is strongly detectable by whole-mount in situ hybridisation [11, 14].”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
tfec is co-expressed with ltk during iridoblast fate choice and iridophore differentiation.
“As we showed previously [14], tfec is co-expressed with the established iridophore marker, ltk [11], during iridoblast fate choice and iridophore differentiation.”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
Analysis of ltk expression in sox10 mutants indicated the presence of an ltk+ precursor of pigment cells, consistent with the chromatoblast.
“More recently, analysis of ltk expression in sox10 mutants indicated the presence of an ltk+ precursor of pigment cells, consistent with the chromatoblast [11].”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
ltk mutants do not show an analogous late increase in melanocytes.
“Interestingly, despite the similarity between tfec and ltk mutant iridophore phenotypes, ltk mutants do not show an analogous late increase in melanocytes [11].”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [11]
ltk expression shows two phases: one in early neural crest development representing a multipotent chromatoblast-like progenitor, and a second in the definitive iridophore lineage.
“We have shown that ltk expression appears to show two phases, one in early NC development which we propose represents a multipotent, chromatoblast-like progenitor, and a second in the definitive iridophore lineage [9].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
Sox10 and the receptor tyrosine kinase Ltk play crucial roles in iridophore specification.
“In the case of iridophores, as well as Sox10, the receptor tyrosine kinase Leukocyte tyrosine kinase (Ltk) plays a crucial role”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
tfec is a definitive marker of differentiated iridophores at 72 hpf.
“WISH on single embryos at 72 hpf confirmed that tfec is a definitive marker of differentiated iridophores (Fig 1A), similar to the established iridophore lineage marker, ltk [9].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
tfec, pnp4a and sox10 show multiphasic expression similar to that previously noted for ltk.
“We had first noted this in our study of ltk expression [9], but here we showed that tfec, pnp4a and sox10 behave similarly.”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
In the sox10 mutant context, Sox10, Tfec and Ltk acquire positive values, but Mitfa and Pnp4a do not become upregulated.
“In the sox10 mutant context we asked that Sox10, Tfec and Ltk acquire positive values, as expression has been identified in trapped chromatoblasts ([9], [26] and this work), however at no point do either Mitfa or Pnp4a become upregulated.”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
Premigratory cells of the ARPT that express tfec, no longer foxd3, and later upregulate other pigment markers are multipotent iridophore progenitors corresponding to the proposed partially restricted pigment cell progenitor.
“We consider that these premigratory cells of the Anterior Region of the Posterior Trunk (ARPT; Fig 1B) which express tfec, but no longer foxd3, and which only later detectably upregulate other pigment markers, are multipotent iridophore progenitors corresponding to the proposed partially restricted pigment cell progenitor [9].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
mitfa and ltk are activated widely by 22 hpf, with pnp4a following soon after.
“However, mitfa and ltk are activated widely by 22 hpf [9], [19], with pnp4a following soon after [15].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
For all three versions of model A, simulation of loss of Sox10 function predicted maintenance of tfec and ltk, consistent with observations that tfec+;ltk+ progenitors remain trapped in the dorsal trunk and tail.
“For all three versions of model A, simulation of loss of Sox10 function appropriately predicted maintenance of tfec (Fig 3B) and of ltk [9], consistent with observations that tfec+;ltk+ progenitors remain trapped in the dorsal trunk and tail.”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
In sox10 mutants, NCCs become trapped in the Cbl state.
“In sox10 mutants, we suggest that NCCs become trapped in the Cbl state, since specification to all non-ectomesenchymal fates is blocked [9], [26], [52].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [9]
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Cited by
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D’Agati, G., Beltre, R., Sessa, A., Burger, A., Zhou, Y., Mosimann, C., & White, R. M. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.07.017 · Cited by 87 · see citing works
Petratou, K., Subkhankulova, T., Lister, J. A., Rocco, A., Schwetlick, H., & Kelsh, R. N. (2018) · PLOS Genetics · doi:10.1371/journal.pgen.1007402 · Cited by 69 · see citing works
Self-citationPetratou, K., Spencer, S. A., Kelsh, R. N., & Lister, J. A. (2021) · PLOS ONE · doi:10.1371/journal.pone.0244794 · Cited by 55 · see citing works
Self-citationHuang, D., Kapadia, E. H., Liang, Y., Shriver, L. P., Dai, S., Patti, G. J., Humbel, B. M., Laudet, V., & Parichy, D. M. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2424180122 · Cited by 15 · see citing works
- Authors
- Lopes, S. S., Yang, X., Müller, J., Carney, T. J., McAdow, A. R., Rauch, G.-J., Jacoby, A. S., Hurst, L. D., Delfino-Machín, M., Haffter, P., Geisler, R., Johnson, S. L., Ward, A., & Kelsh, R. N.
- Affiliations
- University of Bath (GB)
- Washington University in St. Louis (US)
- Max Planck Institute for Developmental Biology (DE)
- Corresponding author
- Kelsh, Robert N.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-03-07
- Volume
- 4
- Issue
- 3
- Pages
- e1000026
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2265441
- OpenAlex
- W2150242706
- Cited by
- 163
- References
- 0
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 4 · 2021: 22 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 16 · 2016: 10 · 2015: 9 · 2014: 10 · 2013: 12 · 2012: 10
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- The University of Bath Online Publications Store (The University of Bath) (submittedVersion, cc-by)
- Pure (University of Bath) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- National Institutes of Health
- Medical Research Council
- National Institute of General Medical Sciences (GM56988, R01GM056988, R56GM056988)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- LTK, iridophores, neural crest cells, SOX10, pigment cell development, cell fate specification, zebrafish, melanocytes, cell-autonomous signaling, cell transplantation, cell migration
- MeSH terms
- Alleles, Animals, Carrier Proteins, Chromosome Mapping, High Mobility Group Proteins, Leukocytes, Melanocytes, Models, Biological, Mutation, Neural Crest, Phylogeny, Protein-Tyrosine Kinases, Zebrafish, Apoptosis, Gene Expression Regulation, Developmental, Zebrafish Proteins, Multipotent Stem Cells, Embryonic Stem Cells, SOXE Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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