Developmental Heterogeneity Research Articles

Isolation of mononuclear phagocytes from the mouse gut.

The intestinal tract is home to trillions of microbes that make up the gut microbiota and is a major source of environmental antigens that can be derived from food, commensal microorganisms, and potential pathogens. Amidst this complex environment, myeloid cells, including macrophages (MPs) and dendritic cells (DCs), are key immunological sentinels that locally maintain both tissue and immune homeostasis. Recent research has revealed substantial functional and developmental heterogeneity within the intestinal DC and MP compartments, with evidence pointing to their regulation by the microbiota. DCs are classically divided into three subsets based on their CD103 and CD11b expression: CD103+CD11b-(XCR1+) cDC1s, CD103+CD11b+ cDC2s, and CD103-CD11b+ cDC2s. Meanwhile, mature gut MPs have recently been classified by their expression of Tim-4 and CD4 into a long-lived, self-maintaining Tim-4+CD4+ population and short-lived, monocyte-derived Tim-4-CD4+ and Tim-4-CD4- populations. In this chapter, we provide experimental procedures to classify and isolate these myeloid subsets from the murine intestinal lamina propria for functional characterization.

Heterogeneities in Cognitive and Socio-Emotional Development in Children With Autism Spectrum Disorder and Severe Intellectual Disability as a Comorbidity.

Introduction: Intellectual disability (ID) is frequently associated as a comorbidity in autism spectrum disorders (ASD). This study investigated a) how similar the heterogeneity in the cognitive and socio-emotional developmental profiles was for children with ASD and ID, b) the difference between the subjects’ profiles and those of typically developing children (TD) matched for developmental levels, c) the skills existing with the lowest and highest developmental levels, and d) the relationship between developmental profiles in ASD and the severity of autism, ID, and the overall developmental level. Participants: The sample was comprised of 119 children (101 boys and 18 girls) who ranged in chronological age (CA) from 21 months to 14 years (M = 5 years 2 months; SD = 2 years 6 months) with developmental levels lower than 24 months. They came from three countries (France = 40, Brazil = 40, and Algeria = 39). The control group was comprised of 40 TD children from these same countries who ranged in CA from 4 to 24 months (M = 1 year 3 months; SD = 5 months). The ASD diagnosis was carried out according to International Statistical Classification of Diseases and Related Health Problems-10th Edition (ICD-10), Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), Diagnostic and Statistical Manual of Mental Disorders-5th ed (DSM-5) criteria and the Childhood Autism Rating Scale (CARS). Measures: Children were tested using the Social Cognitive Evaluation Battery (SCEB; Adrien, 2007) by trained psychologists from public and private institutions specialized in the diagnosis of autism and interventions in this field. The SCEB explores 16 functional abilities, in both cognitive and socio-emotional areas, and allows the calculation of domain and area developmental levels and heterogeneity indices for the global, cognitive, and socio-emotional areas. Results: Children with ASD developmental profiles show very high heterogeneity as opposed to TD children. Regardless of the country of origin, there are similarities between the heterogeneous cognitive and socio-emotional developmental profiles of the children with ASD, whose profiles are characterized by lower developmental levels of language and vocal imitation skills, and a relationship between these developmental heterogeneities and the degree of severity of autistic symptomatology, intellectual disability, and overall development level. The implications of this study are presented for clinical assessment and intervention purposes in ASD and ID.

Childhood multi-trajectories of shyness, anxiety and depression: Associations with adolescent internalizing problems

This study tested the specificity of associations between childhood multi-trajectories of shyness, anxiety and depression symptoms and adolescent social phobia, generalized anxiety disorder (GAD) and depression, as well as functional impairment. A population sample of 1596 singletons was followed over 15 years. Mothers rated child shyness, anxiety and depression between 1½ and 8 years-old. Adolescents self-reported symptoms of social phobia, GAD and depression at 15 years-old. Multi-trajectories of childhood internalizing symptoms showed developmental heterogeneity. Controlling for perinatal risk factors, low anxiety and depression in childhood were associated with lower GAD, depression and impairment in adolescence. Higher childhood shyness was associated with adolescent social phobia. Higher shyness in girls was a protective factor for GAD, depression and impairment due to depression, while low shyness in boys was linked to higher risk for GAD and impairment due to depression. Our results underline the importance of distinguishing between shyness and different internalizing symptoms.

Developmental Heterogeneity in Social Support Among Juvenile Offenders: Relevance of Social Support Withdrawal for the Dulling of Maturational Decline in Offending

Social support is a highly relevant predictor of offending. Despite this, little research has examined how this construct develops over time and how withdrawal of social support may result in “late bloomer” offending. This study used the Pathways to Desistance to data to test hypotheses related to these research questions. Group-based trajectory modeling was used to identify trajectories of social support, and ordinary least squares regression was used to determine the relevance of trajectory group assignment for predicting differences in offending between adolescence and adulthood. Results indicated that withdrawal of social support resulted in a dulling of the maturational decline in offending frequency typically observed following adolescence. Implications are discussed.

Dual lineage tracing identifies intermediate mesenchymal stage for endocardial contribution to fibroblasts, coronary mural cells, and adipocytes

Early embryonic endocardium undergoes endothelial-to-mesenchymal transition to form cardiac cushion mesenchymal cells (MCs). Embryonic endocardium also gives rise to fibroblasts, intramyocardial adipocytes, and coronary mural cells, including smooth muscle cells and pericytes, in development. Whether endocardial cells directly differentiate into fibroblasts, coronary mural cells, and adipocytes or indirectly via an intermediate stage of endocardial-derived cushion MCs remains unknown. In addition to endocardium, epicardium and neural crest also contribute to cardiac cushion MCs. Given the developmental heterogeneity of cushion MCs and the lack of specific markers for endocardial-derived cushion MCs, conventional genetic lineage tracing utilizing Cre recombinase driven by one specific regulatory element is not sufficient to examine the fates of endocardial-derived cushion MCs. Intersectional genetic targeting approaches, which combine regulatory elements from two or more genes, have been employed to increase the specificity of cell targeting. Here, we developed a dual-recombinase intersectional targeting approach using Nfatc1-Dre, Sox9-CreER, and Cre/Dre double-dependent reporter Ai66 to specifically label endocardial-derived cushion MCs. Taking advantage of intersectional lineage tracing, we found that a subset of cardiac cells including fibroblasts, coronary mural cells, and intramyocardial adipocytes in adult hearts were derived from endocardial-derived cushion MCs. Our study suggests that embryonic endocardium contributes to cushion MCs first, and then endocardial-derived cushion MCs migrate into myocardium and differentiate into fibroblasts, coronary mural cells, and adipocytes in development. Understanding developmental origins of cardiac cell lineages will provide us more insights into cardiac development, regeneration, and diseases.

Deciphering White Adipose Tissue Heterogeneity.

Adipose tissue not only stores energy, but also controls metabolism through secretion of hormones, cytokines, proteins, and microRNAs that affect the function of cells and tissues throughout the body. Adipose tissue is organized into discrete depots throughout the body, and these depots are differentially associated with insulin resistance and increased risk of metabolic disease. In addition to energy-dissipating brown and beige adipocytes, recent lineage tracing studies have demonstrated that individual adipose depots are composed of white adipocytes that are derived from distinct precursor populations, giving rise to distinct subpopulations of energy-storing white adipocytes. In this review, we discuss this developmental and functional heterogeneity of white adipocytes both between and within adipose depots. In particular, we will highlight findings from our recent manuscript in which we find and characterize three major subtypes of white adipocytes. We will discuss these data relating to the differences between subcutaneous and visceral white adipose tissue and in relationship to previous work deciphering adipocyte heterogeneity within adipose tissue depots. Finally, we will discuss the possible implications of adipocyte heterogeneity may have for the understanding of lipodystrophies.

Mechanisms of human FoxP3+ Treg cell development and function in health and disease.

SummaryRegulatory T (Treg) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage‐defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non‐suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers such as CD25 and FoxP3. Moreover, murine Treg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff) cells. However, this plasticity can also result in Treg cell lineage instability and acquisition of proinflammatory Teff cell functions. Consequently, these dysfunctional CD4+FoxP3+ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to Treg cell antigen‐specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3+ Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.

The Development of Romantic Partner Involvement and Tolerance of Deviance among Juvenile Offenders: Relevance for Offending Behaviors in Early Adulthood

ABSTRACT This study sought to elucidate heterogeneity in developmental patterns of romantic relationship characteristics and examine the relevance of patterns for predicting offending in adulthood. Group-based trajectory modeling was used to elucidate trajectory groups describing developmental heterogeneity of odds of having a romantic partner and romantic partners’ tolerance of deviance. Poisson regression was used to estimate the effects of group assignments for predicting offending. Three- and four-group models best fit the romantic partner characteristics data. Consistently high odds of having a romantic partner and consistently seeking partners with high tolerance for deviance was associated with greater offending frequency in adulthood.

Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing

Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of developmentand adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.

Developmental and functional heterogeneity of white adipocytes within a single fat depot.

Recent studies suggest that, even within a single adipose depot, there may be distinct subpopulations of adipocytes. To investigate this cellular heterogeneity, we have developed multiple conditionally immortalized clonal preadipocyte lines from white adipose tissue of mice. Analysis of these clones reveals at least three white adipocyte subpopulations. These subpopulations have differences in metabolism and differentially respond to inflammatory cytokines, insulin, and growth hormones. These also have distinct gene expression profiles and can be tracked by differential expression of three marker genes: Wilms' tumor 1, transgelin, and myxovirus 1. Lineage tracing analysis with dual-fluorescent reporter mice indicates that these adipocyte subpopulations have differences in gene expression and metabolism that mirror those observed in the clonal cell lines. Furthermore, preadipocytes and adipocytes from these subpopulations differ in their abundance in different fat depots. Thus, white adipose tissue, even in a single depot, is comprised of distinct subpopulations of white adipocytes with different physiological phenotypes. These differences in adipocyte composition may contribute to the differences in metabolic behavior and physiology of different fat depots.

Linkages between geochemistry and microbiology in a proglacial terrain in the High Arctic

ABSTRACTProglacial environments are ideal for studying the development of soils through the changes of rocks exposed by glacier retreat to weathering and microbial processes. Carbon (C) and nitrogen (N) contents as well as soil pH and soil elemental compositions are thought to be dominant factors structuring the bacterial, archaeal and fungal communities in the early stages of soil ecosystem formation. However, the functional linkages between C and N contents, soil composition and microbial community structures remain poorly understood. Here, we describe a multivariate analysis of geochemical properties and associated microbial community structures between a moraine and a glaciofluvial outwash in the proglacial area of a High Arctic glacier (Longyearbreen, Svalbard). Our results reveal distinct differences in developmental stages and heterogeneity between the moraine and the glaciofluvial outwash. We observed significant relationships between C and N contents,δ13Corgandδ15N isotopic ratios, weathering and microbial abundance and community structures. We suggest that the observed differences in microbial and geochemical parameters between the moraine and the glaciofluvial outwash are primarily a result of geomorphological variations of the proglacial terrain.

Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors.

Obesity rates and the burden of metabolic associated diseases are escalating worldwide Energy burning brown and inducible beige adipocytes in human adipose tissues (ATs) have attracted considerable attention due to their therapeutic potential to counteract the deleterious metabolic effects of nutritional overload and overweight. Recent research has highlighted the relevance of resident and recruited ATs immune cell populations and their signalling mediators, cytokines, as modulators of the thermogenic activity of brown and beige ATs. In this review, we first provide an overview of the developmental, cellular and functional heterogeneity of the AT organ, as well as reported molecular switches of its heat-producing machinery. We also discuss the key contribution of various interleukins signalling pathways to energy and metabolic homeostasis and their roles in the biogenesis and function of brown and beige adipocytes. Besides local actions, attention is also drawn to their influence in the central nervous system (CNS) networks governing energy expenditure.

Functional and Developmental Heterogeneity in Human Adipose Tissue Depots

Obesity results from the accumulation of excess white adipose tissue, and its increasing rates worldwide pose a significant risk to overall health due to its multiple comorbidities, like type 2 diabetes. A novel treatment strategy is to increase energy expenditure through activation of brown and beige adipocytes, which can use uncoupling protein 1 (UCP1) for thermogenesis. In addition to having different developmental lineages, brown and beige adipocytes differ functionally regarding the additional mechanisms by which they generate heat. Most human fat depots are not easily accessible, so little is known about their developmental and functional characteristics. In this study, we collected adipose tissue from 11 patients (age 16-84, 4 female/7 male) who had undergone autopsy. We sampled from 7 anatomically distinct fat depots: subcutaneous (sc), omental (om), retroperitoneal (rp), pericardial (pc), periadrenal (pa), paraspinal (ps), and supraclavicular (sv). We measured mRNA levels of lineage and functional genes associated with brown, beige, and white adipocytes. Energy storing white adipocytes were defined by high leptin expression, while energy expending brown and beige cells were defined by high UCP1; these were further distinguished as having a brown lineage using Zic1 and beige via Tbx1. Principal component analysis showed three different clusters of genes consistent with the brown, beige, and white lineages. Functionally, based on expression of leptin and UCP1 for white and brown fat, respectively, the sc and om were white (P<0.05), while rp, pc, pa, ps, and sv were mostly brown (P<0.05). Regarding lineage of the UCP1+ depots, ps had both beige and brown cells, while rp, pa, ps, and sv were predominantly brown. In summary, human adipose tissue is not merely white or brown but instead is composed of many depots with distinct developmental lineages and functional capacities. These differences will be important when trying to use brown and beige adipocyte thermogenesis to treat obesity and diabetes. Disclosure J.W. Johnson: None. C. Cero: None. A. O'Mara: None. J.D. Linderman: None. A.S. Baskin: None. A. Cypess: None.

Examining Developmental Adversity and Connectedness in Child Welfare-Involved Children

Identifying optimal out-of-home placements for child welfare-involved youth is challenging. Examples of youth recovering within each “out-of-home” placement type (foster, relative, residential) are evident, as are examples of youth who are deteriorating. The heterogeneity in developmental history and current functioning of youth makes blanket policies regarding placement unwise. Examination of developmental heterogeneity and functioning of youth in the welfare system can provide insights about factors influencing outcomes, thereby informing practice, program and policy. We explore whether current relational health (connectedness) promotes positive outcomes for child welfare-involved youth while controlling for developmental risk (history of adverse, and lack of relationally positive, experiences). Clinicians at 19 organisations serving child welfare-involved youth used a neurodevelopmentally informed approach to intervention, the Neurosequential Model of Therapeutics (NMT), which includes metrics to assess the developmental timing of children's risk, “connectedness” and neurodevelopmental functioning (e.g., sleep, arousal, cortical control). Data-driven statistical techniques were used to produce stable, generalisable estimates. Risk during the perinatal (0–2 months) period significantly predicted children's functioning; current relational health predicted outcomes more strongly. Although early life developmental risk has a persistent effect on functioning, relationally supportive contexts may mitigate this risk. Improving relational contexts of child welfare-involved youth, regardless of placement type, is key.

Clec9a-Mediated Ablation of Conventional Dendritic Cells Suggests a Lymphoid Path to Generating Dendritic Cells In Vivo.

Conventional dendritic cells (cDCs) are versatile activators of immune responses that develop as part of the myeloid lineage downstream of hematopoietic stem cells. We have recently shown that in mice precursors of cDCs, but not of other leukocytes, are marked by expression of DNGR-1/CLEC9A. To genetically deplete DNGR-1-expressing cDC precursors and their progeny, we crossed Clec9a-Cre mice to Rosa-lox-STOP-lox-diphtheria toxin (DTA) mice. These mice develop signs of age-dependent myeloproliferative disease, as has been observed in other DC-deficient mouse models. However, despite efficient depletion of cDC progenitors in these mice, cells with phenotypic characteristics of cDCs populate the spleen. These cells are functionally and transcriptionally similar to cDCs in wild type control mice but show somatic rearrangements of Ig-heavy chain genes, characteristic of lymphoid origin cells. Our studies reveal a previously unappreciated developmental heterogeneity of cDCs and suggest that the lymphoid lineage can generate cells with features of cDCs when myeloid cDC progenitors are impaired.

The Relevance of Victimization Experiences for Predicting the Development of Threat Symptoms During Adolescence and Early Adulthood.

The "threat" portion of the threat/control override symptom constellation is characterized by the belief by an individual that others seek to do them harm. There has yet to be an examination of the link between perceived threat symptomatology and the experience of victimization, despite the fact that both constructs are linked to the perpetration of violent behavior. Furthermore, there has yet to be research which examines the heterogeneity in developmental patterns of threat symptomatology. The present research utilized the Pathways to Desistance data to model the developmental heterogeneity in perceived threat symptomatology across adolescence and early adulthood using group-based trajectory modeling. A series of multinomial logistic regression models were then estimated to examine the relevance of victimization experiences for predicting trajectory group assignment. A five-group model of development during adolescence and early adulthood best fit the threat symptom data. Victimization experienced prior to age 16 predicted assignment to all groups in the model characterized by presentation of threat symptoms at some point during the study. Victimization experienced between ages 16 and 23 predicted assignment to the High Chronic group and marginally predicted assignment to the Accelerating group. These results indicate that victimization does indeed predict the presentation of perceived threat symptomatology. This indicates that presentation of threat symptoms may be indicative of a history of victimization. Proper screening of those presenting threat symptoms may help to better orient treatment plans for modalities centered on victimization experiences. Future research should investigate the possibility that threat symptoms mediate the relationship between victimization and violent behavior.

Quantifying floristic and structural forest maturity: An attribute‐based method for wet eucalypt forests

Abstract Maintaining developmental heterogeneity of ecological communities within landscapes is crucial for sustainable native forest management. Consequently, methods to assess forest maturity (i.e. the degree to which the forest contains attributes and supports processes characteristic of late‐successional forests) are valuable for making management decisions. However, no consistent, pragmatic method to quantify maturity that incorporates multiple ecosystem elements is available for many forest systems, including Australian wet eucalypt forests. We draw upon forest community dynamics theory to develop a method to quantify maturity based on forest attributes, and use this method to create two metrics of wet eucalypt forest floristic and structural maturity. We then test the ability of remotely sensed and field‐collected variables to predict these metrics. Both the floristic and structural maturity metrics performed well at capturing underlying trends of forest maturation. Remotely sensed LiDAR (Light Detection and Ranging) and photo‐interpretation data provided estimates of moderate accuracy for both floristic and structural maturity (R2 = .57–.77). Field variables that are relatively efficient and accurate to measure provided greater model accuracy (R2 = .73–.85). Including more complex field variables increased model accuracy to high levels (R2 = .93). Therefore, while maturity predicted from remote‐sensing data enables a useful and accessible large‐scale maturity measure, field indices would provide a more accurate means of assessing maturity at the local stand level. Synthesis and applications. The metrics developed in this study provide a powerful tool for undertaking consistent assessments of wet eucalypt forest maturity. This assessment tool could improve forest management by providing information to optimise practices such as prioritising stands for retention or harvesting, determining the effectiveness of restoration or management practices and monitoring changes in maturity over time. The method could be adapted to any forest system that undergoes well‐defined directional development.

Heterogeneity of adipose tissue in development and metabolic function.

Adipose tissue is a central metabolic organ. Unlike other organs, adipose tissue is compartmentalized into individual depots and distributed throughout the body. These different adipose depots show major functional differences and risk associations for developing metabolic syndrome. Recent advances in lineage tracing demonstrate that individual adipose depots are composed of adipocytes that are derived from distinct precursor populations, giving rise to different populations of energy-storing white adipocytes. Moreover, distinct lineages of energy-dissipating brown and beige adipocytes exist in discrete depots or within white adipose tissue depots. In this Review, we discuss developmental and functional heterogeneity, as well as sexual dimorphism, between and within individual adipose tissue depots. We highlight current data relating to the differences between subcutaneous and visceral white adipose tissue in the development of metabolic dysfunction, with special emphasis on adipose tissue expansion and remodeling of the extracellular matrix. Moreover, we provide a detailed overview of adipose tissue development as well as the consensus and controversies relating to adult adipocyte precursor populations.

Single-cell RNA sequencing reveals developmental heterogeneity of blastomeres during major genome activation in bovine embryos

Embryonic development is initially controlled by maternal RNAs and proteins stored in the oocyte, until gene products gradually generated by the embryo itself take over. Major embryonic genome activation (EGA) in bovine embryos occurs at the eight- to 16-cell stage. Morphological observations, such as size of blastomeres and distribution of microvilli, suggested heterogeneity among individual cells already at this developmental stage. To address cell heterogeneity on the transcriptome level, we performed single-cell RNA sequencing of 161 blastomeres from 14 in vitro produced bovine embryos at Day 2 (n = 6) and Day 3 (n = 8) post fertilization. Complementary DNA libraries were prepared using the Single-Cell RNA-Barcoding and Sequencing protocol and sequenced. Non-supervised clustering of single-cell transcriptome profiles identified six clusters with specific sets of genes. Most embryos were comprised of cells from at least two different clusters. Sorting cells according to their transcriptome profiles resulted in a non-branched pseudo-time line, arguing against major lineage inclination events at this developmental stage. In summary, our study revealed heterogeneity of transcriptome profiles among single cells in bovine Day 2 and Day 3 embryos, suggesting asynchronous blastomere development during the phase of major EGA.

Heterogeneity in the development of proactive and reactive aggression in childhood: Common and specific genetic - environmental factors.

BackgroundFew studies are grounded in a developmental framework to study proactive and reactive aggression. Furthermore, although distinctive correlates, predictors and outcomes have been highlighted, proactive and reactive aggression are substantially correlated. To our knowledge, no empirical study has examined the communality of genetic and environmental underpinning of the development of both subtypes of aggression. The current study investigated the communality and specificity of genetic-environmental factors related to heterogeneity in proactive and reactive aggression’s development throughout childhood.MethodsParticipants were 223 monozygotic and 332 dizygotic pairs. Teacher reports of aggression were obtained at 6, 7, 9, 10 and 12 years of age. Joint development of both phenotypes were analyzed through a multivariate latent growth curve model. Set point, differentiation, and genetic maturation/environmental modulation hypotheses were tested using a biometric decomposition of intercepts and slopes.ResultsCommon genetic factors accounted for 64% of the total variation of proactive and reactive aggression’s intercepts. Two other sets of uncorrelated genetic factors accounted for reactive aggression’s intercept (17%) on the one hand, and for proactive (43%) and reactive (13%) aggression’s slopes on the other. Common shared environmental factors were associated with proactive aggression’s intercept (21%) and slope (26%) and uncorrelated shared environmental factors were also associated with reactive aggression’s slope (14%). Common nonshared environmental factors explained most of the remaining variability of proactive and reactive aggression slopes.ConclusionsA genetic differentiation hypothesis common to both phenotypes was supported by common genetic factors associated with the developmental heterogeneity of proactive and reactive aggression in childhood. A genetic maturation hypothesis common to both phenotypes, albeit stronger for proactive aggression, was supported by common genetic factors associated with proactive and reactive aggression slopes. A shared environment set point hypothesis for proactive aggression was supported by shared environmental factors associated with proactive aggression baseline and slope. Although there are many common features to proactive and reactive aggression, the current research underscores the advantages of differentiating them when studying aggression.