High Expression of Doublecortin and KIAA0369 Protein in Fetal Brain Suggests Their Specific Role in Neuronal Migration

Mizuguchi, Masashi; Qin, Jiong; Yamada, Mitsunori; Ikeda, Kazuhiko; Takashima, Sachio

doi:10.1016/s0002-9440(10)65486-7

Cited by 61 publications

(38 citation statements)

References 20 publications

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“…In the developing cortex, DCLK is most strongly expressed in cortical plate neurons (4), whereas some reports show expression in migrating neurons (5,49). We plan to use the anti-DCLK phospho-Ser-382 antibodies to study the distribution of phosphorylated DCLK within the brain and to study the pattern of phosphorylation of this residue in response to stimulation protocols in cultured neurons.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Burgess

Reiner

2002

Journal of Biological Chemistry

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Alternative splicing of mRNA transcripts expands the range of protein products from a single gene locus. Several splice variants of DCLK (doublecortin-like kinase) have previously been reported. Here, we report the genomic organization underlying the splice variants of DCLK and examine the expression profile of two splice variants affecting the kinase domain of DCLK and CPG16 (candidate plasticity gene 16), one containing an Arg-rich domain and the other affecting the C terminus of the protein. These splice alternatives were differentially expressed in embryonic and adult brain. Both splice variants disrupted DCLK PEST domains; however, all splice variants remained sensitive to proteolysis by calpain. The adult-specific C-terminal splice variant of DCLK had reduced autophosphorylation activity, but similar kinase activity for myelin basic protein relative to the embryonic splice variant. The splice variant adding an Arg-rich domain gained an autophosphorylation site at Ser-382. Although this protein isoform was expressed mainly in the adult brain, the phosphorylated form was strongly enriched in embryonic brain and adult olfactory bulb, suggesting a possible role in migrating neurons.The majority of neuronal cells in the central nervous system are generated during embryogenesis and persist throughout life without further rounds of division and differentiation. Individual neurons accomplish an array of distinct tasks during their life span, including cellular migration, axon extension and pathfinding, synaptogenesis, and participation in mature nervous system function. It has been suggested that to deal with these diverse demands on cellular function, the repertoire of neuronal gene products is enhanced by alternative splicing and RNA editing. Following the description of differential RNA processing of the calcitonin gene (1), alternative splice forms of many gene products have been detected in the central nervous system (2, 3). Doublecortin-like kinase (DCLK) 1 is a serine-threonine kinase expressed in the central nervous system. The N-terminal domain of DCLK is very similar to the doublecortin protein and mediates microtubule localization (4 -6). The C-terminal kinase domain of DCLK resembles members of the family of calcium/calmodulin-dependent protein kinases, but lacks a canonical calmodulin-binding site (7). The human gene was named DCAMKL1 (doublecortin-and Ca 2ϩ /calmodulindependent protein kinase-like protein-1) (8); however, biochemical evidence does not indicate that calcium/calmodulin modulates kinase activity (7).The DCLK locus gives rise to several transcripts through differential splicing and use of alternative promoters (see Fig. 1). The DCL product includes the doublecortin domain, but lacks the kinase domain. DCLK Rϩ is a full-length transcript embracing both doublecortin and kinase domains and includes an additional 16 amino acids enriched in arginine residues (the Arg-rich domain), between the doublecortin and kinase domains (9). Two splice variants affecting the final coding exon of DCLK hav...

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Section: Discussionmentioning

confidence: 99%

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Burgess

Reiner

2002

Journal of Biological Chemistry

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“…DCLK expression is widespread during the period of embryonic brain development and down-regulated thereafter (14,17,25). During this time, DCLK immunoreactivity is seen in neuronal cell bodies and neurites, but is strikingly enhanced in growth cones (11).…”

Section: Discussionmentioning

confidence: 99%

“…The appearance of a 50-kDa band in transfected 293-T cells that is of similar size to that found in cultured neurons suggests that the neuronal 50-kDa band is derived from DCLK and is not merely a cross-reactive protein. Furthermore, Mizuguchi et al (25) noted a 35-kDa band cross reactive to their anti-DCLK Nterminal antibody in human fetal brain extracts. As the Cterminal 50-kDa band and the N-terminal 35-kDa band appear under the same conditions in 293-T cells and have a combined molecular mass the size of the full-length DCLK protein, we wondered whether these peptides may be derived by proteolytic cleavage of the FLAG-DCLK protein at the boundary of the doublecortin domain and the ST-rich domain (the cleavage A site in Fig.…”

Section: Truncated Forms Of Dclk Are Observed In Primary Cultured Neumentioning

confidence: 99%

Cleavage of Doublecortin-like Kinase by Calpain Releases an Active Kinase Fragment from a Microtubule Anchorage Domain

Burgess

Reiner

2001

Journal of Biological Chemistry

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Doublecortin-like kinase (DCLK) is widely expressed in postmitotic neurons throughout the embryonic nervous system. DCLK consists of an N-terminal doublecortin domain, responsible for its localization to microtubules, and a C-terminal serine-threonine kinase domain. Here we report that DCLK is a physiological substrate for the cysteine protease calpain. Cleavage of DCLK by calpain severs the kinase domain from its microtubule anchorage domain and releases it into the cytoplasm. The isolated kinase domain retains catalytic activity and is structurally similar to CPG16, a second product of the DCLK gene expressed in the adult brain that lacks the doublecortin domain. We propose that in neurons cleavage of DCLK by calpain represents a calciumresponsive mechanism to regulate localization of the DCLK kinase domain.

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“…These immature neurons were defined in brain sections that had been immunolabeled with doublecortin, a tubulin-associated protein expressed in migrating neuroblasts [Jessberger and Kempermann, 2003;Kempermann et al, 2003;Mizuguchi et al, 1999;Nacher et al, 2001] ( fig. 8 A-F).…”

Section: Immature Neurons Are Reduced In the Subgranular Zone After Tmentioning

confidence: 99%

Traumatic Injury to the Immature Brain Results in Progressive Neuronal Loss, Hyperactivity and Delayed Cognitive Impairments

Pullela

Raber

Pfankuch³

et al. 2006

Dev Neurosci

118

135

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The immature brain may be particularly vulnerable to injury during critical periods of development. To address the biologic basis for this vulnerability, mice were subjected to traumatic brain injury at postnatal day 21, a time point that approximates that of the toddler-aged child. After motor and cognitive testing at either 2 weeks (juveniles) or 3 months (adults) after injury, animals were euthanized and the brains prepared for quantitative histologic assessment. Brain-injured mice exhibited hyperactivity and age-dependent anxiolysis. Cortical lesion volume and subcortical neuronal loss were greater in brain-injured adults than in juveniles. Importantly, cognitive decline was delayed in onset and coincided with loss of neurons in the hippocampus. Our findings demonstrate that trauma to the developing brain results in a prolonged period of pathogenesis in both cortical and subcortical structures. Behavioral changes are a likely consequence of regional-specific neuronal degeneration.

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High Expression of Doublecortin and KIAA0369 Protein in Fetal Brain Suggests Their Specific Role in Neuronal Migration

Cited by 61 publications

References 20 publications

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Alternative Splice Variants of Doublecortin-like Kinase Are Differentially Expressed and Have Different Kinase Activities

Cleavage of Doublecortin-like Kinase by Calpain Releases an Active Kinase Fragment from a Microtubule Anchorage Domain

Traumatic Injury to the Immature Brain Results in Progressive Neuronal Loss, Hyperactivity and Delayed Cognitive Impairments

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