Developmental Etiology Research Articles

A novel ciliopathic skull defect arising from excess neural crest

The skull is essential for protecting the brain from damage, and birth defects involving disorganization of skull bones are common. However, the developmental trajectories and molecular etiologies by which many craniofacial phenotypes arise remain poorly understood. Here, we report a novel skull defect in ciliopathic Fuz mutant mice in which only a single bone pair encases the forebrain, instead of the usual paired frontal and parietal bones. Through genetic lineage analysis, we show that this defect stems from a massive expansion of the neural crest-derived frontal bone. This expansion occurs at the expense of the mesodermally-derived parietal bones, which are either severely reduced or absent. A similar, though less severe, phenotype was observed in Gli3 mutant mice, consistent with a role for Gli3 in cilia-mediated signaling. Excess crest has also been shown to drive defective palate morphogenesis in ciliopathic mice, and that defect is ameliorated by reduction of Fgf8 gene dosage. Strikingly, skull defects in Fuz mutant mice are also rescued by loss of one allele of fgf8, suggesting a potential route to therapy. In sum, this work is significant for revealing a novel skull defect with a previously un-described developmental etiology and for suggesting a common developmental origin for skull and palate defects in ciliopathies.

Aetiological influences on stability and change in emotional and behavioural problems across development: a systematic review.

Emotional and behavioural problems in childhood and adolescence can be chronic and are predictive of future psychiatric problems. Understanding what factors drive the development and maintenance of these problems is therefore crucial. Longitudinal behavioural genetic studies using twin, sibling or adoption data can be used to explore the developmental aetiology of stability and change in childhood and adolescent psychopathology. We present a systematic review of longitudinal, behavioural genetic analyses of emotional and behavioural problems between ages 0 to 18 years. We identified 58 studies, of which 19 examined emotional problems, 30 examined behavioural problems, and 9 examined both. In the majority of studies, stability in emotional and behavioural problems was primarily genetically influenced. Stable environmental factors were also widely found, although these typically played a smaller role. Both genetic and environmental factors were involved in change across development. We discuss the findings in the context of the wider developmental literature and make recommendations for future research.

Using mouse and zebrafish models to understand the etiology of developmental defects in Cornelia de Lange Syndrome.

Cornelia de Lange Syndrome (CdLS) is a multisystem birth defects disorder that affects every tissue and organ system in the body. Understanding the factors that contribute to the origins, prevalence, and severity of these developmental defects provides the most direct approach for developing screens and potential treatments for individuals with CdLS. Since the majority of cases of CdLS are caused by haploinsufficiency for NIPBL (Nipped-B-like, which encodes a cohesin-associated protein), we have developed mouse and zebrafish models of CdLS by using molecular genetic tools to create Nipbl-deficient mice and zebrafish (Nipbl(+/-) mice, zebrafish nipbl morphants). Studies of these vertebrate animal models have yielded novel insights into the developmental etiology and genes/gene pathways that contribute to CdLS-associated birth defects, particularly defects of the gut, heart, craniofacial structures, nervous system, and limbs. Studies of these mouse and zebrafish CdLS models have helped clarify how deficiency for NIPBL, a protein that associates with cohesin and other transcriptional regulators in the nucleus, affects processes important to the emergence of the structural and physiological birth defects observed in CdLS: NIPBL exerts chromosome position-specific effects on gene expression; it influences long-range interactions between different regulatory elements of genes; and it regulates combinatorial and synergistic actions of genes in developing tissues. Our current understanding is that CdLS should be considered as not only a cohesinopathy, but also a "transcriptomopathy," that is, a disease whose underlying etiology is the global dysregulation of gene expression throughout the organism. © 2016 Wiley Periodicals, Inc.

A life course perspective on familial and environmental risks for schizophrenia using a western Australian E-cohort

IntroductionFamilial risk for psychosis may interact with environmental risk factors.ObjectivesWe are studying a large birth cohort of children of mothers with psychotic disorders, themselves at high risk of developing a psychotic illness, to understand the developmental aetiology of psychotic illness.AimsOur aim is to examine whether exposure to environmental stressors in childhood, including timing of exposure, is a risk factor for psychotic illness, independent of familial liability. Specificity to maternal schizophrenia is explored.MethodsWe used record-linkage across state-wide registers (midwives, psychiatric, child protection and mortality, among others) to identify 15,486 offspring born in Western Australia 1980–2001 to mothers with a lifetime history of psychotic illness (case children) and compared them with 452,459 offspring born in the same period to mothers with no known psychiatric history (comparison children).ResultsA total of 4.1% of case children had developed a psychotic illness compared to 1.1% of comparison children. Exposure to environmental risk factors including obstetric complications, aboriginality, lower socioeconomic status, discontinuity in parenting and childhood abuse significantly increased risk of psychotic illness in offspring. Length and age at time of discontinuity in parenting impacted on risk. At the same time, case children were also significantly more likely than comparison children to be at risk of experiencing these adverse life events.ConclusionsExposure to environmental stressors is associated with psychotic illness, and timing of exposure is important. However, children already at increased familial risk for psychotic illness are also at increased risk of experiencing these environmental stressors.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Etiological Influences on Perceptions of Parenting: A Longitudinal, Multi-Informant Twin Study.

Children and their parents often differ in their perception of the relationship they share. As this relationship changes developmentally, the nature of these differences may also change. Longitudinal genetic designs can be used to investigate the developmental etiologies of shared and distinct perceptions. In this study, we used longitudinal psychometric models to analyze child and parent reports of negative parenting for 6417 twin pairs from the Twins Early Development Study at ages 9, 12 and 14 years. Within-time cross-reporter correlations, indicating the degree to which children and parents perceived negative parenting behaviors similarly at each age, were moderate (r = .44 − .46). Longitudinal genetic analyses revealed these shared perceptions to be relatively stable during the transition into adolescence, with this stability driven by a combination of children’s genetic factors and family-wide environmental factors. In contrast, child- and parent-specific perceptions of parenting were predominantly age-specific, a developmental pattern underpinned by child genetic factors and a combination of family-wide and unique environmental influences. These results and their implications are discussed in the context of interplay between reciprocal interactions, subjective insight and developmental behavioral change in the parent–child relationship.

Abstract 16541: Abnormal Brain Connectivity and Poor Neurodevelopmental Outcome in Congenital Heart Disease Patients With Subtle Brain Dysplasia

Introduction: Mutant mouse models with congenital heart disease (CHD) were observed to have distinct brain dysplasia, prompting an assessment for brain anomalies in CHD patients. CHD infants with brain magnetic resonance imaging (MRI) assessments were recruited and scored using a novel brain dysplasia index. Validation was conducted with parallel brain connectome analysis and neurodevelopment outcome assessments. Methods: The Ohia mutant mouse line and others were analyzed for brain defects using 3D episcopic confocal histopathology. In parallel, we recruited 220 CHD neonates with MRI scans from two large centers. This included pre and postoperative conventional MRI sequences and diffusion tensor imaging (DTI). Brain connectivity measurements with DTI-graph analysis and neurodevelopmental testing at 18 months of age (Battelle Developmental Inventory) were obtained. Results: The CHD mouse mutant analysis revealed high prevalence of brain dysplasia involving the olfactory bulb, cerebellum, hippocampus, corpus callosum and choroid plexus. Based on these findings, a brain dysplasia index (BDI) was developed for clinical assessment of CHD patients, with one point for abnormality in any of these structures right or left and for presence of extra-axial cerebral spinal fluid. Analysis of 220 CHD neonates yielded BDI scores ranging from 1 to 17, with average score of 4.1. An elevated BDI score was seen across a spectrum of cardiac lesions, and was similar pre-op and post-op. DTI graph connectivity measurements (reduced nodal efficiency) correlated with high BDI score (p<0.05), but not to specific heart lesions or white matter injury. Neurodevelopmental assessment of 20 patients at 18 months showed higher BDI score correlated with reduction in Total Developmental Quotient (p <0.05) and Adaptive Developmental Quotient (p<0.009). Conclusion: A brain dysplasia index was developed based on brain anomalies seen in CHD mutant mouse models. Infants with CHD of a broad spectrum with high BDI score showed abnormal brain connectivity and poor neurodevelopmental outcome. These findings suggest the poor neurodevelopmental outcome associated with CHD may involve subtle brain dysplasia with a shared developmental etiology with the structural heart disease.

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease.

Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions.

Focal cortical dysplasia in meningioangiomatosis

Meningioangiomatosis is a rare, benign, developmental, or hamartomatous lesion which may involve the leptomeninges and underlying brain parenchyma. Histologically, meningioangiomatosis is marked by a proliferation of blood vessels in the parenchyma, rimmed by collars of spindled meningothelial cells. There are anecdotal reports of an association of meningioangiomatosis with focal cortical dysplasia. We retrospectively analyzed the clinical, histopathologic, and treatment outcomes of 16 patients with a diagnosis of meningioangiomatosis, specifically investigating these cases for evidence of adjacent focal cortical dysplasia. Patients ranged in age from 1 to 34 years (median 18), 12 of whom had medically-intractable epilepsy as their presenting symptom. No patients in this study had a confirmed diagnosis of neurofibromatosis type II. Four patients (25%) were found to have fibrous meningiomas associated with the meningioangiomatosis. Ten of the 12 patients (83%) who had adequate tissue excised adjacent to the meningioangiomatosis demonstrated evidence of focal cortical dysplasia, with 6 of those (60%) classified as Palmini type IA, and 4 patients (40%) classified as Palmini type IIA. Seven of the patients (44%) had no post-operative seizures, and were off anti-epileptic drugs, while 2 patients relapsed, and required pharmacologic treatment for seizure control. This study therefore presents evidence to support inclusion of meningioangiomatosis as a focal cortical dysplasia-associated entity, as suggested by the ILAE classification (type IIIc). As focal cortical dysplasia is a developmental malformation, its association with meningioangiomatosis supports a developmental etiology of sporadic meningioangiomatosis.

Hemispherectomy for treatment of refractory epilepsy in the pediatric age group: a systematic review.

Evidence in support of hemispherectomy stems from a multitude of retrospective studies illustrating individual institutions' experience. A systematic review of this topic, however, is lacking in the literature. A systematic review of hemispherectomy for the treatment of refractory epilepsy available up to October 2013 was performed using the following inclusion criteria: reports of a total of 10 or more patients in the pediatric age group (≤ 20 years) undergoing hemispherectomy, seizure outcome reported after a minimum follow-up of 1 year after the initial procedure, and description of the type of hemispherectomy. Only the most recent paper from institutions that published multiple papers with overlapping study periods was included. Two reviewers independently applied the inclusion criteria and extracted all the data. Twenty-nine studies with a total of 1161 patients met the inclusion criteria. Seizure outcome was available for 1102 patients, and the overall rate of seizure freedom at the last follow-up was 73.4%. Sixteen studies (55.2%) exclusively reported seizure outcomes of a single type of hemispherectomy. There was no statistically significant difference in seizure outcome and type of hemispherectomy (p = 0.737). Underlying etiology was reported for 85.4% of patients with documented seizure outcome, and the overall distribution of acquired, developmental, and progressive etiologies was 30.5%, 40.7%, and 28.8%, respectively. Acquired and progressive etiologies were associated with significantly higher seizure-free rates than developmental etiologies (p < 0.001). Twenty of the 29 studies (69%) reported complications. The overall rate of hydrocephalus requiring CSF diversion was 14%. Mortality within 30 days was 2.2% and was not statistically different between types of hemispherectomy (p = 0.787). Hemispherectomy is highly effective for treating refractory epilepsy in the pediatric age group, particularly for acquired and progressive etiologies. While the type of hemispherectomy does not have any influence on seizure outcome, hemispherotomy procedures are associated with a more favorable complication profile.

Bulls′ teeth: An insight through CBCT

Taurodontism is a morphologic alteration in the shape of the tooth, in which there is an enlargement of the pulp chamber with apical displacement of the pulpal floor and lack of the normal constriction at the level of the cemento-enamel junction. Although its developmental etiology is evidential and well documented, it occurs as a part of multiple syndromes as well as several developmental anomalies. This review compiles different facets of origin of taurodontism, rather than viewing it just as a developmental malformation, cited so far in the literature. A case report in which all the first permanent molars are being affected with taurodontism is also presented.

Loss of dopamine D2 receptors increases parvalbumin-positive interneurons in the anterior cingulate cortex.

Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders.

Mental health antecedents of early midlife insomnia: evidence from a four-decade longitudinal study.

Insomnia is a highly prevalent condition that constitutes a major public health and economic burden. However, little is known about the developmental etiology of adulthood insomnia. We examined whether indicators of psychological vulnerability across multiple developmental periods (psychiatric diagnoses in young adulthood and adolescence, childhood behavioral problems, and familial psychiatric history) predicted subsequent insomnia in adulthood. We used data from the ongoing Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort study of 1,037 children in New Zealand who were followed prospectively from birth (1972-1973) through their fourth decade of life with a 95% retention rate. Insomnia was diagnosed at age 38 according to DSM-IV criteria. Psychiatric diagnoses, behavioral problems, and family psychiatric histories were assessed between ages 5 and 38. In cross-sectional analyses, insomnia was highly comorbid with multiple psychiatric disorders. After controlling for this concurrent comorbidity, our results showed that individuals who have family histories of depression or anxiety, and who manifest lifelong depression and anxiety beginning in childhood, are at uniquely high risk for age-38 insomnia. Other disorders did not predict adulthood insomnia. The link between lifelong depression and anxiety symptoms and adulthood insomnia calls for further studies to clarify the neurophysiological systems or behavioral conditioning processes that may underlie this association.

Viewing behavior and related clinical characteristics in a population of children with visual impairments in the Netherlands

Children with visual impairments are very heterogeneous in terms of the extent of visual and developmental etiology. The aim of the present study was to investigate a possible correlation between prevalence of clinical risk factors of visual processing impairments and characteristics of viewing behavior. We tested 149 children with visual information processing impairments (90 boys, 59 girls; mean age (SD)=7.3 (3.3)) and 127 children without visual impairments (63 boys and 64 girls, mean age (SD)=7.9 (2.8)). Visual processing impairments were classified based on the time it took to complete orienting responses to various visual stimuli (form, contrast, motion detection, motion coherence, color and a cartoon). Within the risk group, children were divided into a fast, medium or slow group based on the response times to a highly salient stimulus. The relationship between group specific response times and clinical risk factors was assessed. The fast responding children in the risk group were significantly slower than children in the control group. Within the risk group, the prevalence of cerebral visual impairment, brain damage and intellectual disabilities was significantly higher in slow responding children compared to faster responding children. The presence of nystagmus, perceptual dysfunctions, mean visual acuity and mean age did not significantly differ between the subgroups. Orienting responses are related to risk factors for visual processing impairments known to be prevalent in visual rehabilitation practice. The proposed method may contribute to assessing the effectiveness of visual information processing in children.

Redox Regulation and the Autistic Spectrum: Role of Tryptophan Catabolites, Immuno-inflammation, Autoimmunity and the Amygdala.

The autistic spectrum disorders (ASD) form a set of multi-faceted disorders with significant genetic, epigenetic and environmental determinants. Oxidative and nitrosative stress (O&NS), immuno-inflammatory pathways, mitochondrial dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway play significant interactive roles in driving the early developmental etiology and course of ASD. O&NS interactions with immuno-inflammatory pathways mediate their effects centrally via the regulation of astrocyte and microglia responses, including regional variations in TRYCATs produced. Here we review the nature of these interactions and propose an early developmental model whereby different ASD genetic susceptibilities interact with environmental and epigenetic processes, resulting in glia biasing the patterning of central interarea interactions. A role for decreased local melatonin and N-acetylserotonin production by immune and glia cells may be a significant treatment target.

Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy

Dilated cardiomyopathy (DCM) due to mutations in RBM20, a gene encoding an RNA-binding protein, is associated with high familial penetrance, risk of progressive heart failure and sudden death. Although genetic investigations and physiological models have established the linkage of RBM20 with early-onset DCM, the underlying basis of cellular and molecular dysfunction is undetermined. Modeling human genetics using a high-throughput pluripotent stem cell platform was herein designed to pinpoint the initial transcriptome dysfunction and mechanistic corruption in disease pathogenesis. Tnnt2-pGreenZeo pluripotent stem cells were engineered to knockdown Rbm20 (shRbm20) to determine the cardiac-pathogenic phenotype during cardiac differentiation. Intracellular Ca(2+) transients revealed Rbm20-dependent alteration in Ca(2+) handling, coinciding with known pathological splice variants of Titin and Camk2d genes by Day 24 of cardiogenesis. Ultrastructural analysis demonstrated elongated and thinner sarcomeres in the absence of Rbm20 that is consistent with human cardiac biopsy samples. Furthermore, Rbm20-depleted transcriptional profiling at Day 12 identified Rbm20-dependent dysregulation with 76% of differentially expressed genes linked to known cardiac pathology ranging from primordial Nkx2.5 to mature cardiac Tnnt2 as the initial molecular aberrations. Notably, downstream consequences of Rbm20-depletion at Day 24 of differentiation demonstrated significant dysregulation of extracellular matrix components such as the anomalous overexpression of the Vtn gene. By using the pluripotent stem cell platform to model human cardiac disease according to a stage-specific cardiogenic roadmap, we established a new paradigm of familial DCM pathogenesis as a developmental disorder that is patterned during early cardiogenesis and propagated with cellular mechanisms of pathological cardiac remodeling.

Height, adiposity and hormonal cardiovascular risk markers in childhood: how to partition the associations?

Objective:Obesity is associated with rapid growth during childhood. There is uncertainty over how to adjust for body size, when using adiposity as a proxy for cardiovascular risk. We studied associations of height, body composition (by dual-energy X-ray absorptiometry) and cardiovascular risk markers (insulin resistance (IR), leptin) in children.Methods:Using partial correlations in 172 children aged 7–12 years, we investigated associations of (a) fat mass with IR or leptin, adjusting for height or lean mass, and (b) height or lean mass with IR or leptin, adjusting for fat mass. Analyses were conducted both cross-sectionally at each age, and for changes between 7 and 12 years.Results:Height, fat mass, lean mass, IR and leptin were all inter-correlated at all ages. Although fat mass was strongly associated with IR and leptin, height was independently negatively associated with leptin (whole sample, adjusting for age: boys r=−0.12, girls r=−0.13; P<0.001). Independent of adiposity, height was also associated with insulin IR (whole sample, adjusting for age: boys r=0.11, girls r=0.20; P<0.001). When analysed by year of age, these associations tended to remain significant at older ages. Change in height from 7 to 12 years was also associated with change in IR (boys: r=0.18, P<0.05; girls: r=0.34, P<0.01), independently of change in adiposity, with similar findings for lean mass.Conclusions:During childhood, markers of cardiovascular risk have a complex profile, associated with growth as well as fat accumulation. Taller and faster-growing children have elevated risk markers, independently of their adiposity. These findings have implications for the interpretation of pediatric indices of adiposity that aim to adjust for body size. Adiposity indices that perform best at summarizing metabolic risk may not be those that perform best at understanding the developmental aetiology of risk.

Face recognition deficits in autism spectrum disorders are both domain specific and process specific.

Although many studies have reported face identity recognition deficits in autism spectrum disorders (ASD), two fundamental question remains: 1) Is this deficit “process specific” for face memory in particular, or does it extend to perceptual discrimination of faces as well? And 2) Is the deficit “domain specific” for faces, or is it found more generally for other social or even nonsocial stimuli? The answers to these questions are important both for understanding the nature of autism and its developmental etiology, and for understanding the functional architecture of face processing in the typical brain. Here we show that children with ASD are impaired (compared to age and IQ-matched typical children) in face memory, but not face perception, demonstrating process specificity. Further, we find no deficit for either memory or perception of places or cars, indicating domain specificity. Importantly, we further showed deficits in both the perception and memory of bodies, suggesting that the relevant domain of deficit may be social rather than specifically facial. These results provide a more precise characterization of the cognitive phenotype of autism and further indicate a functional dissociation between face memory and face perception.

Imaging techniques for visualizing and phenotyping congenital heart defects in murine models

Mouse model is ideal for investigating the genetic and developmental etiology of congenital heart disease. However, cardiovascular phenotyping for the precise diagnosis of structural heart defects in mice remain challenging. With rapid advances in imaging techniques, there are now high throughput phenotyping tools available for the diagnosis of structural heart defects. In this review, we discuss the efficacy of four different imaging modalities for congenital heart disease diagnosis in fetal/neonatal mice, including noninvasive fetal echocardiography, micro-computed tomography (micro-CT), micro-magnetic resonance imaging (micro-MRI), and episcopic fluorescence image capture (EFIC) histopathology. The experience we have gained in the use of these imaging modalities in a large-scale mouse mutagenesis screen have validated their efficacy for congenital heart defect diagnosis in the tiny hearts of fetal and newborn mice. These cutting edge phenotyping tools will be invaluable for furthering our understanding of the developmental etiology of congenital heart disease.

Development of the diaphragm – a skeletal muscle essential for mammalian respiration

The mammalian diaphragm muscle is essential for respiration, and thus is one of the most critical skeletal muscles in the human body. Defects in diaphragm development leading to congenital diaphragmatic hernias (CDH) are common birth defects and result in severe morbidity or mortality. Given its functional importance and the frequency of congenital defects, an understanding of diaphragm development, both normally and during herniation, is important. We review current knowledge of the embryological origins of the diaphragm, diaphragm development and morphogenesis, as well as the genetic and developmental aetiology of diaphragm birth defects.

Mapping Developmental Precursors of Cyber-Aggression: Trajectories of Risk Predict Perpetration and Victimization

Technologically mediated contexts are social arenas in which adolescents can be both perpetrators and victims of aggression. Yet, there remains little understanding of the developmental etiology of cyber aggression, itself, as experienced by either perpetrators or victims. The current study examines 3-year latent within-person trajectories of known correlates of cyber-aggression: problem behavior, (low) self-esteem, and depressed mood, in a large and diverse sample of youth (N = 1,364; 54.6% female; 12-14 years old at T1). Findings demonstrate that developmental increases in problem behavior across grades 8-10 predict both cyber-perpetration and victimization in grade 11. Developmental decreases in self-esteem also predicted both grade 11 perpetration and victimization. Finally, early depressed mood predicted both perpetration and victimization later on, regardless of developmental change in depressed mood in the interim. Our results reveal a clear link between risky developmental trajectories across the early high school years and later cyber-aggression and imply that mitigating trajectories of risk early on may lead to decreases in cyber-aggression at a later date.