Spatial and temporal diversity of DCLK1 isoforms in developing mouse brain

Bergoglio, Emilia; Suzuki, Ikuo; Togashi, Katsumi; Tsuji, Michiko; Takeuchi, Shunsuke; Koizumi, Hiroyuki; Emoto, Kazuo

doi:10.1016/j.neures.2020.12.004

Cited by 5 publications

(4 citation statements)

References 49 publications

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“…We have here identified two splice variants of NvDclk1, with NvDclk1s lacking the C-terminal kinase domain. Similar splice variants have been recovered for Dclk genes in mice [83,84]. The NvDclk1 mutant presented here truncates the protein in the first dcx domain.…”

Section: Discussionsupporting

confidence: 77%

Doublecortin-like kinase is required for cnidocyte development in Nematostella vectensis

Kraus,

Busengdal,

Kraus

et al. 2024

Neural Dev

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The complex morphology of neurons requires precise control of their microtubule cytoskeleton. This is achieved by microtubule-associated proteins (MAPs) that regulate the assembly and stability of microtubules, and transport of molecules and vesicles along them. While many of these MAPs function in all cells, some are specifically or predominantly involved in regulating microtubules in neurons. Here we use the sea anemone Nematostella vectensis as a model organism to provide new insights into the early evolution of neural microtubule regulation. As a cnidarian, Nematostella belongs to an outgroup to all bilaterians and thus occupies an informative phylogenetic position for reconstructing the evolution of nervous system development. We identified an ortholog of the microtubule-binding protein doublecortin-like kinase (NvDclk1) as a gene that is predominantly expressed in neurons and cnidocytes (stinging cells), two classes of cells belonging to the neural lineage in cnidarians. A transgenic NvDclk1 reporter line revealed an elaborate network of neurite-like processes emerging from cnidocytes in the tentacles and the body column. A transgene expressing NvDclk1 under the control of the NvDclk1 promoter suggests that NvDclk1 localizes to microtubules and therefore likely functions as a microtubule-binding protein. Further, we generated a mutant for NvDclk1 using CRISPR/Cas9 and show that the mutants fail to generate mature cnidocytes. Our results support the hypothesis that the elaboration of programs for microtubule regulation occurred early in the evolution of nervous systems.

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Section: Discussionsupporting

confidence: 77%

Doublecortin-like kinase is required for cnidocyte development in Nematostella vectensis

Kraus,

Busengdal,

Kraus

et al. 2024

Neural Dev

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“…These results suggest M6 plays a critical role in AD pathogenesis by metabolically interacting with neurons [ 57 ]. The M2 ECM module had increased expression of ECM-associated genes (e.g., CD44 , TNC , and VCAN ) and protein kinases ( DCLK1/2 ) that were involved in radial migration and axon growth of cortical neurons and associated with neurodevelopmental and neuropsychiatric disorders [ 58 , 59 ]. Additionally, GLIS3 in the M2 module has been studied to influence the glioma cells’ invasion, migration, and proliferation and upregulate the NF-κB signaling pathway [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Integration of Single-Cell RNA-Seq Data Reveals Astrocyte Diversity and Transcriptomic Modules across Six Central Nervous System Disorders

et al. 2023

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The dysfunction of astrocytes in response to environmental factors contributes to many neurological diseases by impacting neuroinflammation responses, glutamate and ion homeostasis, and cholesterol and sphingolipid metabolism, which calls for comprehensive and high-resolution analysis. However, single-cell transcriptome analyses of astrocytes have been hampered by the sparseness of human brain specimens. Here, we demonstrate how large-scale integration of multi-omics data, including single-cell and spatial transcriptomic and proteomic data, overcomes these limitations. We created a single-cell transcriptomic dataset of human brains by integration, consensus annotation, and analyzing 302 publicly available single-cell RNA-sequencing (scRNA-seq) datasets, highlighting the power to resolve previously unidentifiable astrocyte subpopulations. The resulting dataset includes nearly one million cells that span a wide variety of diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), epilepsy (Epi), and chronic traumatic encephalopathy (CTE). We profiled the astrocytes at three levels, subtype compositions, regulatory modules, and cell–cell communications, and comprehensively depicted the heterogeneity of pathological astrocytes. We constructed seven transcriptomic modules that are involved in the onset and progress of disease development, such as the M2 ECM and M4 stress modules. We validated that the M2 ECM module could furnish potential markers for AD early diagnosis at both the transcriptome and protein levels. In order to accomplish a high-resolution, local identification of astrocyte subtypes, we also carried out a spatial transcriptome analysis of mouse brains using the integrated dataset as a reference. We found that astrocyte subtypes are regionally heterogeneous. We identified dynamic cell–cell interactions in different disorders and found that astrocytes participate in key signaling pathways, such as NRG3-ERBB4, in epilepsy. Our work supports the utility of large-scale integration of single-cell transcriptomic data, which offers new insights into underlying multiple CNS disease mechanisms where astrocytes are involved.

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“…Interestingly, DCLK1 can be proteolytically processed into a shorter form lacking the microtubule binding domains, indicating a possible functional difference between DCX-containing and non-DCX fragments of the protein [92,93]. Moreover, DCLK1 isoforms are differentially expressed and localized in developing mouse brains [94]. This study also showed that DCLK1 isoforms were generated via transcription, indicating regulation by distinct promoters.…”

Section: Dclk1mentioning

confidence: 59%

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

Moore,

Houchen

2023

IJMS

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While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1.

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Spatial and temporal diversity of DCLK1 isoforms in developing mouse brain

Cited by 5 publications

References 49 publications

Doublecortin-like kinase is required for cnidocyte development in Nematostella vectensis

Doublecortin-like kinase is required for cnidocyte development in Nematostella vectensis

Large-Scale Integration of Single-Cell RNA-Seq Data Reveals Astrocyte Diversity and Transcriptomic Modules across Six Central Nervous System Disorders

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

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