Mammalian DSCAMs: roles in the development of the spinal cord, cortex, and cerebellum?

doi:10.1016/S0006-291X(02)00307-8

Biochemical and Biophysical Research Communications

Volume 293, Issue 3, 10 May 2002, Pages 881-891

https://doi.org/10.1016/S0006-291X(02)00307-8 Get rights and content

Abstract

Central nervous system (CNS) development involves neural patterning, neuronal and axonal migrations, and synapse formation. DSCAM, a chromosome 21 axon guidance molecule, is expressed by CNS neurons during development and throughout adult life. We now report that DSCAM and its chromosome 11 paralog DSCAML1 exhibit inverse ventral–dorsal expression patterns in the developing spinal cord and distinct, partly inverse, expression patterns in the developing cortex, beginning in the Cajal–Retzius cells. In the adult cortex, DSCAM predominates in layer 3/5 pyramidal cells and DSCAML1 predominates in layer 2 granule cells. In the cerebellum, DSCAM is stronger in the Purkinje cells and DSCAML1 in the granule cells. Finally, we find that the predicted DSCAML1 protein contains 60 additional N-terminal amino acids which may contribute to its distinct expression pattern and putative function. We propose that the DSCAMs comprise novel elements of the pathways mediating dorsal–ventral patterning and cell-fate specification in the developing CNS.

Section snippets

Materials and methods

Tissue in situ hybridization. RT-PCR products corresponding to human DSCAML1 Probes 1, 2, 3, and 4 and mouse DscamL1 Probe M1 (see Fig. 1A) were subcloned in pBluescript (Stratagene) and used to prepare DSCAML1 cRNA probes, as described previously [5]. DSCAM cRNA probes were prepared from the mouse Dscam cDNA clone CHD2M-14. The labelled fragments were used independently as probes on serial sections of normal mouse embryos from embryonic day (E) 10.5 through E18.5 and on serial sections of

DSCAM and DSCAML1 exhibit inverse dorsal–ventral expression patterns in the developing spinal cord

To determine the relationship of DSCAM and DSCAML1 patterns of expression during development, tissue in situ hybridization (TISH) analyses were performed on serial sagittal sections of normal mouse embryos at E12.5, using a human DSCAML1 PCR product (Probe 2, see Fig. 1A) and mouse Dscam cDNA CHD2-M14 [5] as probes (see Materials and methods). These analyses revealed strikingly different patterns of expression for DSCAM and DSCAML1 in the developing spinal cord, with DSCAM expression

Discussion

In this report we have shown that DSCAM, a putative axon guidance molecule mapping to chromosome 21 [5], [7], and its recently identified homolog DSCAML1[8], are expressed in complementary patterns in the developing spinal cord and cortex. Based on these results, we propose that the DSCAMs may be involved in mediating dorsal–ventral distinctions in the developing spinal cord at the time of neurite extension and may also be involved in mediating regional neuronal fates in the developing cortex.

Acknowledgements

The authors wish to thank Dr. Harvey Sarnat and Dr. Laura Flores-Sarnat for the helpful discussions during the preparation of the manuscript. This work was supported by NHLBI Grant HL61033 and NICHD Grant HD17449. JRK holds the Geri and Richard Brawerman Chair of Molecular Genetics. GEL is an established investigator of the American Heart Association and is supported by a grant from the American Heart Association WI Affiliate.

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Down syndrome (DS) is caused by triplication of chromosome 21 (HSA21). It is characterised by intellectual disability and impaired motor coordination that arise from changes in brain volume, structure and function. However, the contribution of each HSA21 gene to these various phenotypes and to the causal alterations in neuronal and synaptic structure and function are largely unknown. Here we have investigated the effect of overexpression of the HSA21 gene DSCAM (Down syndrome cell adhesion molecule), on glutamatergic synaptic transmission and motor coordination, using Drosophila expressing three copies of Dscam1. Electrophysiological recordings of miniature and evoked excitatory junction potentials at the glutamatergic neuromuscular junction of Drosophila larvae showed that the extra copy of Dscam1 changed the properties of spontaneous and electrically-evoked transmitter release and strengthened short-term synaptic depression during high-frequency firing of the motor nerve. Behavioural analyses uncovered impaired locomotor coordination despite preserved gross motor function. This work identifies DSCAM as a candidate causative gene in DS that is sufficient to modify synaptic transmission and synaptic plasticity and cause a DS behavioural phenotype.
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Spatial patterns of neuronal connectivity are critical for neural circuit function and information processing. For many neuron types, the development of stereotyped dendritic and axonal territories involves reiterative contacts between neurites and successive re-calibration of branch outgrowth and directionality. Here I review emerging roles for members of the atypical cadherins (Fmi/Celsrs) and the clustered Protocadherins (Pcdhs) in neurite patterning. These cell-surface molecules have shared functions: they engage in homophilic recognition and mediate dynamic and contact-dependent interactions to establish reproducible and space-filling arborization patterns. As shown in genetic and molecular studies, the atypical cadherins and clustered Pcdhs serve in multiple contexts and signal diverse actions such as neurite repulsion or selective adhesion. In some cell types, they regulate the non-overlapping arrangement of branches achieved through homotypic interactions, such as in self-avoidance or tiling. In others, they promote dendritic complexity through cell–cell interactions. With critical roles in both the fine-scale arrangement of axonal and dendritic branching and the large-scale organization of axon tracts and neuronal networks, the atypical cadherins and clustered Pcdhs are key regulators of neural circuit assembly and function.
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Citation Excerpt :
Thus, DSCAM and DSCAML1 play similar but important roles in the development of mouse cortical neurons. Previous studies showed that DSCAM and DSCAML1 are widely expressed in developing and adult mouse brain, including the cerebral cortex (Barlow et al., 2002). In order to investigate the functions of these two genes, we firstly examined their expression in the mouse cerebral cortex at postnatal day 7 (P7) using in situ hybridization.
Down syndrome cell adhesion molecule (Dscam) is essential for self-avoidance and tiling of dendritic development in sensory neurons in Drosophila. Recent studies also show that DSCAM together with its closely related protein DSCAML1 functions in dendritic self-avoidance of a certain types of interneuron in mammalian retina. However, the functions of these DSCAMs in developing mammalian cerebral cortex are not well understood. Here we reduced the expression of DSCAM or DSCAML1 in mouse cortical neurons by RNA interference both in vitro and in vivo. We found that knockdown of DSCAM or DSCAML1 increases the complexity of proximal dendritic branching, and impedes the axon growth in cultured neurons. In vivo knockdown experiments showed that both DSCAM and DSCAML1 contribute to normal radial migration and callosal projection during the postnatal development. Our results indicate an important role of DSCAM and DSCAML1 in the development of cortical neural network.
Tyrosine phosphorylation is essential for DSCAML1 to promote dendrite arborization of mouse cortical neurons
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Dendritic self-avoidance is critical for appropriate dendrite arborization. We herein examined the role of Down syndrome cell adhesion molecule like-1 (DSCAML1) in regulating dendritic self-avoidance and that of tyrosine phosphorylation in mediating the effects of DSCAML1. Knocking down DSCAML1 in newborn mouse cortical neurons compromised dendritic self-avoidance as evidenced by dendritic fasciculation and increased dendritic self-crossing. Introduction of a DSCAML1^Y1808F mutant into the DSCAML1-knocked down neurons failed to reverse the abnormal dendritic arborization. These results suggest that DSCAML1 promotes dendritic self-avoidance in cortical neurons, and that phosphorylation at Y1808 is essential in mediating the effects of DSCAML1.
Identification and characterization of DSCAM isoforms isolated from orange-spotted grouper Epinephelus coioides
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The Down syndrome cell adhesion molecule (DSCAM), an immunoglobulin (Ig) superfamily member, was first identified from human and subsequently isolated from both vertebrates and invertebrates. Recent studies have shown that the DSCAM molecule serves diverse functions in neurodevelopment, such as axon guidance and neuronal migration. Most studies on DSCAM, however, have focused on mammals and arthropods, and our present knowledge of bony fish DSCAM is still limited. In this study, orange-spotted grouper Epinephelus coioides was used as an animal model to explore the possible functions of DSCAM. Two DSCAM isoforms were isolated, namely EcDSCAM A and EcDSCAM B, with lengths of 1648 and 2025 amino acids, respectively. The classical domain structure (i.e. 9Ig-4FNIII-1Ig-2FNIII-Transmembrane domain-Cytoplasmic tail) was also found in the coding regions of these two EcDSCAMs. Phylogenetic analysis showed that in the vertebrate DSCAM clade, the EcDSCAMs and various teleost DSCAMs were clustered into a subclade. Real-time PCR revealed that EcDSCAM B is the major EcDSCAM isoform, with the expression of EcDSCAM B being significantly higher than that of EcDSCAM A. During the first 14 days after hatching (dph), increases in the expression of the two EcDSCAMs were observed at 2–4 and 8–11 dph. EcDSCAM is expressed mainly in the intestine, nerve-related tissues, and stomach. Optic nerve transection analysis showed that EcDSCAM was up-regulated during optic nerve regeneration after optic nerve injury. We also investigated whether DSCAM expression was affected by viral nervous necrosis (VNN) disease or vibriosis. We found that when grouper were challenged with nervous necrosis virus (NNV), there were no meaningful changes in DSCAM expression, but challenge with Vibrio anguillarum led to a decrease in EcDSCAM levels in the brain. This decrease may be related to the pathogenesis of V. anguillarum.
Down syndrome cell adhesion molecule (DSCAM) associates with uncoordinated-5C (UNC5C) in netrin-1-mediated growth cone collapse
2012, Journal of Biological Chemistry
In the developing nervous system, neuronal growth cones explore the extracellular environment for guidance cues, which can guide them along specific trajectories toward their targets. Netrin-1, a bifunctional guidance cue, binds to deleted in colorectal cancer (DCC) and DSCAM mediating axon attraction, and UNC5 mediating axon repulsion. Here, we show that DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary cortical neurons and postnatal cerebellar granule cells. DSCAM partially co-localized with UNC5C in primary neurons and brain tissues. Netrin-1 induces axon growth cone collapse of mouse cerebellum external granule layer (EGL) cells, and the knockdown of DSCAM or UNC5C by specific shRNAs or blocking their signaling by overexpressing dominant negative mutants suppresses netrin-1-induced growth cone collapse. Similarly, the simultaneous knockdown of DSCAM and UNC5C also blocks netrin-1-induced growth cone collapse in EGL cells. Netrin-1 increases tyrosine phosphorylation of endogenous DSCAM, UNC5C, FAK, Fyn, and PAK1, and promotes complex formation of DSCAM with these signaling molecules in primary postnatal cerebellar neurons. Inhibition of Src family kinases efficiently reduces the interaction of DSCAM with UNC5C, FAK, Fyn, and PAK1 and tyrosine phosphorylation of these proteins as well as growth cone collapse of mouse EGL cells induced by netrin-1. The knockdown of DSCAM inhibits netrin-induced tyrosine phosphorylation of UNC5C and Fyn as well as the interaction of UNC5C with Fyn. The double knockdown of both receptors abolishes the induction of Fyn tyrosine phosphorylation by netrin-1. Our study reveals the first evidence that DSCAM coordinates with UNC5C in netrin-1 repulsion.

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^☆: Supplementary data for this article are available on IDEAL (http://www.idealibrary.com).

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Mammalian DSCAMs: roles in the development of the spinal cord, cortex, and cerebellum?☆

Abstract

Section snippets

Materials and methods

DSCAM and DSCAML1 exhibit inverse dorsal–ventral expression patterns in the developing spinal cord

Discussion

Acknowledgements

Neuron

Neuron

Cell

Cell

Int. Rev. Cytol.

Cell

Neuron

Neuron

Neuron

Curr. Opin. Neurobiol.

Trends Neurosci.

Cell

Cell

Cell

Neuron

Biochimie

Brain Res. Dev. Brain. Res.

Lancet

Neuron

Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation

Science