Potential involvement of DSCAML1 mutations in neurodevelopmental disorders.

The molecular mechanisms underlying neurodevelopmental disorders (NDDs) remain unclear. We previously identified Down syndrome cell adhesion molecule like 1 (Dscaml1) as a responsible gene for Ihara epileptic rat (IER), a rat model for human NDDs with epilepsy. However, the relationship between NDDs and DSCAML1 in humans is still elusive. In this study, we screened databases of autism spectrum disorders (ASD), intellectual disability (ID)/developmental disorders (DD) and schizophrenia for genomic mutations in human DSCAML1. We then performed in silico analyses to estimate the potential damage to the mutated DSCAML1 proteins and chose three representative mutations (DSCAML1C729R , DSCAML1R1685* and DSCAML1K2108Nfs*37 ), which lacked a cysteine residue in the seventh Ig domain, the intracellular region and the C-terminal PDZ-binding motif, respectively. In overexpression experiments in a cell line, DSCAML1C729R lost its mature N-glycosylation, whereas DSCAML1K2108Nfs*37 was abnormally degraded via proteasome-dependent protein degradation. Furthermore, in primary hippocampal neurons, the ability of the wild-type DSCAML1 to regulate the number of synapses was lost with all mutant proteins. These results provide insight into understanding the roles of the domains in the DSCAML1 protein and further suggest that these mutations cause functional changes, albeit through different mechanisms, that likely affect the pathophysiology of NDDs.

Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.

Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Genetic effects of DSCAML1 identified in genome-wide association study revealing strong associations with litter size and semen quality in goat (Capra hircus).

The down syndrome cell adhesion molecule like 1 (DSCAML1), is associated with the development of the nervous system and neurologic diseases. Previous Genome-wide association studies have shown that it is associated with sperm morphology, suggesting it has a critical role in fecundity. In this study, expression profiles of goat DSCAML1 mRNA were analyzed. The results showed that its expression in the testis differ significantly between the mitotic stage and meiotic stage. Three insertion/deletion (indel) variants of goat DSCAML1 were determined in the Shaanbei White Cashmere Goat (SWCG, n = 2162). Based on the association analysis, two indels (P2-16bp, P14-15bp) were significantly related to sperm quality (sperm motility and sperm density) in male goat and three loci were markedly related to the first-birth litter size in female goat (P = 4.0 × 10-6; P = 1.0 × 10-6; P = 4.7 × 10-2). In male goats, the different genotypes of P2-16bp and P14-15bp revealed a noticeable effect on the expression of DSCAML1. Moreover, the effects observed in the first-birth litter followed a similar trend, which may provide the basis for further research of DSCAML1 gene function and marker assisted selection (MAS) programs to improve reproductive traits.

Subtle Roles of Down Syndrome Cell Adhesion Molecules in Embryonic Forebrain Development and Neuronal Migration.

Down Syndrome (DS) Cell Adhesion Molecules (DSCAMs) are transmembrane proteins of the immunoglobulin superfamily. Human DSCAM is located within the DS critical region of chromosome 21 (duplicated in Down Syndrome patients), and mutations or copy-number variations of this gene have also been associated to Fragile X syndrome, intellectual disability, autism, and bipolar disorder. The DSCAM paralogue DSCAM-like 1 (DSCAML1) maps to chromosome 11q23, implicated in the development of Jacobsen and Tourette syndromes. Additionally, a spontaneous mouse DSCAM deletion leads to motor coordination defects and seizures. Previous research has revealed roles for DSCAMs in several neurodevelopmental processes, including synaptogenesis, dendritic self-avoidance, cell sorting, axon growth and branching. However, their functions in embryonic mammalian forebrain development have yet to be completely elucidated. In this study, we revealed highly dynamic spatiotemporal patterns of Dscam and Dscaml1 expression in definite cortical layers of the embryonic mouse brain, as well as in structures and ganglionic eminence-derived neural populations within the embryonic subpallium. However, an in-depth histological analysis of cortical development, ventral forebrain morphogenesis, cortical interneuron migration, and cortical-subcortical connectivity formation processes in Dscam and Dscaml1 knockout mice (Dscam del17 and Dscaml1 GT ) at several embryonic stages indicated that constitutive loss of Dscam and Dscaml1 does not affect these developmental events in a significant manner. Given that several Dscam- and Dscaml1-linked neurodevelopmental disorders are associated to chromosomal region duplication events, we furthermore sought to examine the neurodevelopmental effects of Dscam and Dscaml1 gain of function (GOF). In vitro, ex vivo, and in vivo GOF negatively impacted neural migration processes important to cortical development, and affected the morphology of maturing neurons. Overall, these findings contribute to existing knowledge on the molecular etiology of human neurodevelopmental disorders by elucidating how dosage variations of genes encoding adhesive cues can disrupt cell-cell or cell-environment interactions crucial for neuronal migration.

Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility.

The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals. Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in one amino acid change in DSCAML1 (A2105T mutation). The mutant DSCAML1A2105T protein is not presented on the cell surface, losing its homophilic cell adhesion ability. We generated knock-in mice (Dscaml1A2105T) carrying the corresponding mutation and observed reduced GABAergic neurons in the ECx as well as spike-and-wave electrocorticogram. We conclude that DSCAML1 is required for GABAergic neuron placement in the ECx and suppression of seizure susceptibility in rodents. Our findings suggest that mutations in DSCAML1 may affect seizure susceptibility in humans.

Tyrosine phosphorylation is essential for DSCAML1 to promote dendrite arborization of mouse cortical neurons.

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.

DSCAMs: restoring balance to developmental forces.

Many of the models of neurodevelopmental processes such as cell migration, axon outgrowth, and dendrite arborization involve cell adhesion and chemoattraction as critical physical or mechanical aspects of the mechanism. However, the prevention of adhesion or attraction is under-appreciated as a necessary, active process that balances these forces, insuring that the correct cells are present and adhering in the correct place at the correct time. The phenomenon of not adhering is often viewed as the passive alternative to adhesion, and in some cases this may be true. However, it is becoming increasingly clear that active signaling pathways are involved in preventing adhesion. These provide a balancing force during development that prevents overly exuberant adhesion, which would otherwise disrupt normal cellular and tissue morphogenesis. The strength of chemoattractive signals may be similarly modulated. Recent studies, described here, suggest that Down Syndrome Cell Adhesion Molecule (DSCAM), and closely related proteins such as DSCAML1, may play an important developmental role as such balancers in multiple systems.