Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity

Hildebrandt, Herbert; Mühlenhoff, Martina; Oltmann-Norden, Imke; Röckle, Iris; Burkhardt, Hannelore; Weinhold, Birgit; Gerardy‐Schahn, Rita

doi:10.1093/brain/awp117

Cited by 69 publications

(67 citation statements)

References 43 publications

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“…Consistent with the previously observed integrity of the internal capsule in mice lacking not only polySia but also its major protein carrier NCAM (Weinhold et al, 2005;Hildebrandt et al, 2009), trajectories of thalamocortical and corticothalamic fibers were normal in the II Ϫ/Ϫ IV Ϫ/Ϫ N Ϫ/Ϫ triple knock-out mice. In line with the proposed mechanism leading to axon tract defects , these findings indicate that thalamocortical misprojection and Rt degeneration are caused by a gain of non-polysialylated NCAM and not by a loss of polySiamediated responses to guidance cues or other polySia-specific functions.…”

Section: Discussionsupporting

confidence: 89%

“…2I). Together, these observations reveal severe guidance defects of thalamocortical and corticothalamic axons in specifically the polySia-negative, NCAMpositive II Ϫ/Ϫ IV Ϫ/Ϫ mice and demonstrate that the loss of these fibers contributes substantially to the hypoplasia of the internal capsule described previously in P1 and in 4-to 6-week-old II (Weinhold et al, 2005;Hildebrandt et al, 2009). …”

Section: IVsupporting

confidence: 79%

“…As shown in mice with genetic ablation of both enzymes, polySia is essential for brain development (Weinhold et al, 2005;Angata et al, 2007). Among other abnormalities, these mice display hypoplasia of major brain axon tracts like anterior commissure, corpus callosum, and internal capsule (Weinhold et al, 2005;Hildebrandt et al, 2009). Axonal defects develop because of a gain of polySia-negative NCAM, as they are not observed in NCAM-negative mice and correlate precisely with the level of NCAM erroneously devoid of polySia during development ).…”

Section: Introductionmentioning

confidence: 91%

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Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice

Schiff¹,

Röckle²,

Burkhardt³

et al. 2011

J. Neurosci.

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IVϪ/Ϫ ) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II Ϫ/Ϫ IV Ϫ/Ϫ mice. Thalamocortical fibers cross the primordium of the reticular thalamic nucleus (Rt) at embryonic day 14.5, before they fail to turn into the ventral telencephalon, thus deviating from their normal trajectory without passing through the internal capsule. At postnatal day 1, a reduction and massive disorganization of fibers traversing the Rt was observed, whereas terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved caspase-3 staining indicated abundant apoptotic cell death of Rt neurons at postnatal day 5. Furthermore, during postnatal development, the number of Rt neurons was drastically reduced in 4-week-old IIN Ϫ/Ϫ triple knock-out animals displaying no internal capsule defects. Thus, degeneration of the Rt in II Ϫ/Ϫ IV Ϫ/Ϫ mice may be a consequence of malformation of thalamocortical and corticothalamic fibers providing major excitatory input into the Rt. Indeed, apoptotic death of Rt neurons could be induced by lesioning corticothalamic fibers on whole-brain slice cultures. We therefore propose that anterograde transneuronal degeneration of the Rt in polysialylation-deficient, NCAM-positive mice is caused by defective afferent innervation attributable to thalamocortical pathfinding defects.

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Section: Discussionsupporting

confidence: 89%

Section: IVsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 91%

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Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice

Schiff¹,

Röckle²,

Burkhardt³

et al. 2011

J. Neurosci.

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“…Simultaneous deletion of NCAM and the polySTs rescues the lethal phenotype, indicating that polysialic acid is required to down-regulate the adhesive properties of NCAM during development (12). In addition, using varying allelic combinations of ST8SiaIV, ST8SiaII, and NCAM, Hildebrandt et al (13) demonstrated that an aberrant increase in the level of unpolysialylated NCAM caused defects in brain connectivity in postnatal day 1 mice.…”

Section: The Neural Cell Adhesion Molecule (Ncam)mentioning

confidence: 99%

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

Foley

Swartzentruber

Thompson

et al. 2010

Journal of Biological Chemistry

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Polysialic acid is a developmentally regulated, anti-adhesive polymer that is added to N-glycans on the fifth immunoglobulin domain (Ig5) of the neural cell adhesion molecule (NCAM). We found that the first fibronectin type III repeat (FN1) of NCAM is required for the polysialylation of N-glycans on the adjacent Ig5 domain, and we proposed that the polysialyltransferases recognize specific sequences in FN1 to position themselves for Ig5 N-glycan polysialylation. Other studies identified a novel FN1 acidic surface patch and ␣-helix that play roles in NCAM polysialylation. Here, we characterize the contribution of two additional FN1 sequences, Pro The neural cell adhesion molecule (NCAM)2 is a member of the immunoglobulin superfamily. It is expressed on the cell surface where it engages in homophilic and heterophilic interactions, resulting in cell adhesion and modulation of signal transduction cascades (reviewed in Refs. 1, 2). In the developing embryo and neonate, NCAM is modified by the addition of long chains of ␣2,8-polysialic acid (3, 4). The presence of this highly hydrated and negatively charged carbohydrate polymer disrupts overall cell adhesion and allows cell migration (5-7). Polysialylation is catalyzed by the polysialyltransferases (polySTs), . NCAM polysialylation is critical during embryogenesis and early postnatal development. Mice that are null for both polySTs are born at Mendelian ratios but have severe neuronal defects, fail to thrive, and the majority die within 4 weeks of birth (12). Simultaneous deletion of NCAM and the polySTs rescues the lethal phenotype, indicating that polysialic acid is required to down-regulate the adhesive properties of NCAM during development (12). In addition, using varying allelic combinations of ST8SiaIV, ST8SiaII, and NCAM, Hildebrandt et al. (13) demonstrated that an aberrant increase in the level of unpolysialylated NCAM caused defects in brain connectivity in postnatal day 1 mice.NCAM is mainly unpolysialylated in the adult brain (3, 4). However, polysialylated NCAM does persist in specific regions of the central nervous system, including the olfactory bulb and hippocampus, where it functions in cell migration, synaptic plasticity, and repair (14 -17). Highly polysialylated NCAM is also re-expressed in several cancers, including neuroblastoma, glioma, small cell and non-small cell lung tumors, and Wilms' tumor, where it has been suggested to promote cancer invasiveness (18 -23). Recently, polysialylated NCAM has been shown to enhance metastasis of a murine model of lung cancer (24) and has been implicated in colorectal carcinoma progression (25). In addition, polysialic acid has been demonstrated to be involved in hematopoietic development (26,27). For example, ST8SiaIV Ϫ/Ϫ mice have reduced thymocyte numbers due to fewer progenitor cells mobilizing to the thymus (27).Although NCAM is by far the most abundant and well documented polysialylated protein, it is striking that only six other polysialylated glycoproteins have been identified. These are the ␣ subu...

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“…Additional studies involving fine structure analysis suggest a comparable quality of polysialylation by ST8SiaII and ST8SiaIV and a distinct synergistic action of the two enzymes in the synthesis of long PSA chains at N-glycosylation site 5 in vivo (Galuska et al, 2008). By analyzing defects in mice with selected combinations of mutant NCAM and polysialyltransferase alleles, Hildebrandt et al (2009) revealed that the extent of the fiber tract deficiencies was not linked to the total amount of PSA or NCAM, but correlated strictly with the level of NCAM erroneously devoid of PSA during brain development. Hence, PSA is the key regulator of central NCAM functions.…”

Section: Polysialylation Controls Plasticity At the Molecular Scale Bmentioning

confidence: 99%

Polysialylation of the Neural Cell Adhesion Molecule: Setting the Stage for Plasticity Across Scales of Biological Organization

Amoureux¹,

Viallat²,

Giribone³

et al. 2012

Chemical Biology

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Imbalance of neural cell adhesion molecule and polysialyltransferase alleles causes defective brain connectivity

Cited by 69 publications

References 43 publications

Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice

Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice

Sequences from the First Fibronectin Type III Repeat of the Neural Cell Adhesion Molecule Allow O-Glycan Polysialylation of an Adhesion Molecule Chimera

Polysialylation of the Neural Cell Adhesion Molecule: Setting the Stage for Plasticity Across Scales of Biological Organization

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