nemo-like kinase is an essential co-activator of Wnt signaling during early zebrafish development
Abstract
Wnt/β-catenin signaling regulates many aspects of early vertebrate development, including patterning of the mesoderm and neurectoderm during gastrulation. In zebrafish, Wnt signaling overcomes basal repression in the prospective caudal neurectoderm by Tcf homologs that act as inhibitors of Wnt target genes. The vertebrate homolog of Drosophila nemo, nemo-like kinase (Nlk), can phosphorylate Tcf/Lef proteins and inhibit the DNA-binding ability of β-catenin/Tcf complexes, thereby blocking activation of Wnt targets. By contrast, mutations in a C. eleganshomolog show that Nlk is required to activate Wnt targets that are constitutively repressed by Tcf. We show that overexpressed zebrafish nlk, in concert with wnt8, can downregulate two tcf3 homologs, tcf3a and tcf3b, that repress Wnt targets during neurectodermal patterning. Inhibition of nlk using morpholino oligos reveals essential roles in regulating ventrolateral mesoderm formation in conjunction with wnt8, and in patterning of the midbrain, possibly functioning with wnt8b. In both instances, nlk appears to function as a positive regulator of Wnt signaling. Additionally, nlk strongly enhances convergent/extension phenotypes associated with wnt11/silberblick, suggesting a role in modulating cell movements as well as cell fate.
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Zebrafish NLK is a positive regulator of Wnt signaling in ventrolateral mesoderm formation and patterning of the midbrain.
“Thorpe et al. revealed that zebrafish NLK appeared to be a positive regulator of Wnt signaling in ventrolateral mesoderm formation and patterning of the midbrain.26)”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [26]
NLK depletion mitigates disease phenotypes in Drosophila and murine models of ALS, murine models of spinobulbar muscular atrophy, and murine models of spinocerebellar ataxia.
“NLK depletion mitigates disease phenotypes not just in Drosophila and murine models of ALS, but also murine models of spinobulbar muscular atrophy, and murine models of spinocerebellar ataxia (15–17).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [15]
Nlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice.
“Conditional Nlk knockout in adult animals is well-tolerated, however (59), and Nlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice (15–18).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [15]
NLK is also likely to act on distinct substrates and disease-related pathways, including the integrated stress response and autophagy.
“RanBP2 and RanGAP1 are two potential targets for NLK with clear connections to nucleocytoplasmic transport, but NLK is also likely to act on distinct substrates and disease-related pathways, including the integrated stress response and autophagy (15).”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [15]
NLK was initially shown to be involved in various developmental processes, such as promotion of mesoderm specification in sea urchins, mesoderm patterning, patterning of midbrain and forebrain in zebrafish, and oocyte maturation in Xenopus Laevis and in mouse testes.
“NLK was initially shown to be involved in various developmental processes, such as the promotion of mesoderm specification in sea urchins [32], mesoderm patterning, patterning of midbrain and forebrain in zebrafish [33], as well as oocyte maturation in Xenopus Laevis [34] and in mouse testes [35].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [33]
Cites
Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation
Heisenberg, C.-P., Tada, M., Rauch, G.-J., Saúde, L., Concha, M. L., Geisler, R., Stemple, D. L., Smith, J. C., & Wilson, S. W. (2000) · Nature · doi:10.1038/35011068 · Cited by 1,013 · see citing works
Ishitani, T., Ninomiya-Tsuji, J., Nagai, S.-I., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H., et al. (1999) · Nature · doi:10.1038/21674 · Cited by 624 · see citing works
Zebrafish trilobite identifies new roles for Strabismus in gastrulation and neuronal movements
Jessen, J. R., Topczewski, J., Bingham, S., Sepich, D. S., Marlow, F., Chandrasekhar, A., & Solnica-Krezel, L. (2002) · Nature Cell Biology · doi:10.1038/ncb828 · Cited by 504 · see citing works
Rotation of photoreceptor clusters in the developing drosophila eye requires the nemo gene
Choi, K.-W., & Benzer, S. (1994) · Cell · doi:10.1016/0092-8674(94)90579-7 · Cited by 339 · see citing works
Dorsky, R. I., Sheldahl, L. C., & Moon, R. T. (2002) · Developmental Biology · doi:10.1006/dbio.2001.0515 · Cited by 287 · cited 3× · see citing works
“…(nlk: 5′-GTGTGTGGTACCTTAAGCAGACAGT3′) were obtained from Gene Tools (Philomath, OR). tcf3b, lef1, wnt8b, wnt11, wnt8 ORF1 and wnt8 ORF2 morpholinos have been previously described (Dorsky et al., 2003; Dorsky et al., 2002; Houart et al., 2002; Lekven et al., 2001; Lele et al., 2001).”
BackgroundMethodSelf-citationIshitani, T., Ninomiya-Tsuji, J., & Matsumoto, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1379-1389.2003 · Cited by 212 · see citing works
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Röttinger, E., Croce, J., Lhomond, G., Besnardeau, L., Gache, C., & Lepage, T. (2006) · Development · doi:10.1242/dev.02603 · Cited by 54 · see citing works
Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies
Daams, R., & Massoumi, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239203 · Cited by 21 · see citing works
“NLK was initially shown to be involved in various developmental processes, such as the promotion of mesoderm specification in sea urchins [32], mesoderm patterning, patterning of midbrain and forebrain in zebrafish [33], as well as oocyte maturation in Xenopus Laevis [34] and in mouse testes [35].”
BackgroundYASUDA, J., & ICHIKAWA, H. (2007) · Proceedings of the Japan Academy, Series B · doi:10.2183/pjab.83.16 · Cited by 6 · see citing works
Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“Among the most consistent and dramatic disease modifiers to emerge from these screens is nemo-like kinase (NLK), a proline-di-rected serine-threonine kinase that regulates cell differentiation, proliferation, and apoptosis (13–15).”
- Authors
- Thorpe, C. J., & Moon, R. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Moon, Randall T.
- ORCID
- Moon, Randall T.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2004-06-15
- Volume
- 131
- Issue
- 12
- Pages
- 2899-2909
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W1999141408
- Cited by
- 84
- References
- 6
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 3 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 1 · 2012: 9
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Renal and related cancers
- Keywords
- Nemo-like kinase, Wnt/β-catenin signaling, TCF/LEF transcription factors, Wnt8, Wnt8b, Wnt11, mesoderm patterning, convergent extension, cell fate specification, zebrafish gastrulation
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Ectoderm, Embryo, Nonmammalian, Gastrula, Molecular Sequence Data, Morphogenesis, Nervous System, Proto-Oncogene Proteins, Zebrafish, Gene Expression Regulation, Enzymologic, Polymerase Chain Reaction, Sequence Alignment, Conserved Sequence, Sequence Homology, Amino Acid, In Situ Hybridization, Gene Expression Regulation, Developmental, Body Patterning, Mitogen-Activated Protein Kinases, Zebrafish Proteins, Wnt Proteins
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