Developmental Tempo Research Articles

A molecular and cellular perspective on human brain evolution and tempo.

The evolution of the modern human brain was accompanied by distinct molecular and cellular specializations, which underpin our diverse cognitive abilities but also increase our susceptibility to neurological diseases. These features, some specific to humans and others shared with related species, manifest during different stages of brain development. In this multi-stage process, neural stem cells proliferate to produce a large and diverse progenitor pool, giving rise to excitatory or inhibitory neurons that integrate into circuits during further maturation. This process unfolds over varying time scales across speciesand has progressivelybecome slower in the human lineage, with differences in tempo correlating with differences in brain size, cell number and diversity, and connectivity. Here we introduce the terms 'bradychrony' and 'tachycrony' to describe slowed and accelerated developmental tempos, respectively. Wereview how recent technical advances across disciplines, including advanced engineering of in vitro models, functional comparative genetics and high-throughput single-cell profiling, are leading to a deeper understanding of how specializationsofthe human brain arise during bradychronic neurodevelopment. Emerging insightspointto a central role for genetics, gene-regulatory networks, cellular innovations and developmental tempo, which together contribute to the establishment of human specializations during various stages of neurodevelopment and at different points in evolution.

Amphibian Segmentation Clock Models Suggest How Large Genome and Cell Sizes Slow Developmental Rate.

Evolutionary increases in genome size, cell volume, and nuclear volume have been observed across the tree of life, with positive correlations documented between all three traits. Developmental tempo slows as genomes, nuclei, and cells increase in size, yet the driving mechanisms are poorly understood. To bridge this gap, we use a mathematical model of the somitogenesis clock to link slowed developmental tempo with changes in intra-cellular gene expression kinetics induced by increasing genome size and nuclear volume. We adapt a well-known somitogenesis clock model to two model amphibian species that vary 10-fold in genome size: Xenopus laevis (3.1 Gb) and Ambystoma mexicanum (32 Gb). Based on simulations and backed by analytical derivations, we identify parameter changes originating from increased genome and nuclear size that slow gene expression kinetics. We simulate biological scenarios for which these parameter changes mathematically recapitulate slowed gene expression in A. mexicanum relative to X. laevis, and we consider scenarios for which additional alterations in gene product stability and chromatin packing are necessary. Results suggest that slowed degradation rates as well as changes induced by increasing nuclear volume and intron length, which remain relatively unexplored, are significant drivers of slowed developmental tempo.

Uncovering developmental time and tempo using deep learning

During animal development, embryos undergo complex morphological changes over time. Differences in developmental tempo between species are emerging as principal drivers of evolutionary novelty, but accurate description of these processes is very challenging. To address this challenge, we present here an automated and unbiased deep learning approach to analyze the similarity between embryos of different timepoints. Calculation of similarities across stages resulted in complex phenotypic fingerprints, which carry characteristic information about developmental time and tempo. Using this approach, we were able to accurately stage embryos, quantitatively determine temperature-dependent developmental tempo, detect naturally occurring and induced changes in the developmental progression of individual embryos, and derive staging atlases for several species de novo in an unsupervised manner. Our approach allows us to quantify developmental time and tempo objectively and provides a standardized way to analyze early embryogenesis.

Interspecies control of development during mammalian gastrulation.

Gastrulation represents a pivotal phase of development and aberrations during this period can have major consequences, from minor anatomical deviations to severe congenital defects. Animal models are used to study gastrulation, however, there is considerable morphological and molecular diversity of gastrula across mammalian species. Here, we provide an overview of the latest research on interspecies developmental control across mammals. This includes single-cell atlases of several mammalian gastrula which have enabled comparisons of the temporal and molecular dynamics of differentiation. These studies highlight conserved cell differentiation regulators and both absolute and relative differences in differentiation dynamics between species. Recent advances in in vitro culture techniques have facilitated the derivation, maintenance and differentiation of cell lines from a range of species and the creation of multi-species models of gastrulation. Gastruloids are three-dimensional aggregates capable of self-organising and recapitulating aspects of gastrulation. Such models enable species comparisons outside the confines of the embryo. We highlight recent in vitro evidence that differentiation processes such as somitogenesis and neuronal maturation scale with known in vivo differences in developmental tempo across species. This scaling is likely due to intrinsic differences in cell biochemistry. We also highlight several studies which provide examples of cell differentiation dynamics being influenced by extrinsic factors, including culture conditions, chimeric co-culture, and xenotransplantation. These collective studies underscore the complexity of gastrulation across species, highlighting the necessity of additional datasets and studies to decipher the intricate balance between intrinsic cellular programs and extrinsic signals in shaping embryogenesis.

A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals.

Differential speeds in biochemical reactions have been proposed to be responsible for the differences in developmental tempo between mice and humans. However, the underlying mechanism controlling the species-specific kinetics remains to be determined. Using invitro differentiation of pluripotent stem cells, we recapitulated the segmentation clocks of diverse mammalian species varying in body weight and taxa: marmoset, rabbit, cattle, and rhinoceros. Together with mouse and human, the segmentation clock periods of the six species did not scale with the animal body weight, but with the embryogenesis length. The biochemical kinetics of the core clock gene HES7 displayed clear scaling with the species-specific segmentation clock period. However, the cellular metabolic rates did not show an evident correlation. Instead, genes involving biochemical reactions showed an expression pattern that scales with the segmentation clock period. Altogether, our stem cell zoo uncovered general scaling laws governing species-specific developmental tempo.

From the fattest to the tallest?

Background: Growth and finally body height are influenced by various intrinsic and extrinsic factors. During the last decades the well documented secular trend of increase in body height slowed down. Overweight and obesity rates increased worldwide from childhood onwards. An association between rising obesity rates and the slowdown of the secular trend in body height might be assumed.
 Aims: This study focuses on patterns of associations between childhood weight status, socioenvironmental factors, and adolescent body height. It is hypothesized that higher weight during childhood enhances developmental tempo and linear growth, and results in higher body height during adolescence.
 Sample and methods: In a longitudinal study, the body height, body weight, and Body mass index (BMI) of 1506 randomly selected Viennese children were documented at the age of six, ten, and fifteen years. Weight status according to sex and age and age-specific BMI percentiles were determined. The association between weight status and body height was analyzed. A history of migration and the socioenvironmental background, based on specific characteristics of the residential area, have been included in the analysis.
 Results: A marked positive association between weight status during childhood, male sex, socioenvironmental factor, the background of migration, and body height at the age of six and ten years could be documented. At the age of fifteen years, however, only male sex and BMI at age ten years were significantly positively associated with height.
 Conclusion: High weight or obesity during childhood enhances growth during childhood, but no significant associations between weight status and height were observable during adolescence.

An increase in the developmental tempo affects the secular trend in height in male Austrian conscripts birth cohorts 1951-2002.

Using population-based data on height in Austria from birth cohort 1951 to 2002, we aim to evaluate the secular trends in height and developmental tempo among Austrian young men. Data were obtained from the Austrian conscription medical examination. We included 1 205 112 conscripts (18-<20 years) who were born between 1951 and 2002 and 853 645 conscripts (17-<19 years) who were born between 1961 and 2002. Height was measured during the medical examination and was used to evaluate the secular trends of mean height over time. Furthermore, the mean difference in height between conscripts of 17- and 18 years old were compared across birth cohorts. The mean height of conscripts aged 17 years increased by 2.2cm (p< .0001) in between 1961 and 2002. The mean height of conscripts aged 18 years increased by 4.3cm (p< .0001) between 1951 and 2002. However, the increase in mean height has slowed down since the 1970 s. The difference in mean height between 17 and 18 years old widened from about 0.1cm in 1961 to 0.3cm around 1970 and then steadily narrowed again to 0.1cm at the end of the study period. The increasing trend in height slows at the end of the 20th century, the developmental tempo at the population level, however, continued to increase. The difference in mean height between 17 and 18 years old narrowed, which may indicate that young men reached their final height earlier.

Growth and Public Health Concerns

Seventeen scientists met for this year’s conference on Auxology held at Krobielowice castle, Poland, to discuss growth and public health concerns. The regulation of growth is complex and besides metabolic and endocrine components including hypothalamic releasing factors, growth hormone and multiple downstream effectors, comprises the full spectrum of the psychosocial, economic and emotional environment including signaling dominance, competence, prestige, or subordination and indulgence, all of this being sensitive to urban or rural lifestyle, the political climate and with marked plasticity throughout history. New statistical techniques (St. Nicolas House Analysis) are presented for analyzing anthropometric variables for public health concerns. The impact of spatial differences on developmental tempo, growth in height, and the prevalence of childhood obesity are discussed as well as the impact of social mobility on obesity, and the benefits of the biopsychosocial status when getting along with socio-economic disasters and the COVID-19 pandemic.

Coupling of growth rate and developmental tempo reduces body size heterogeneity in C. elegans

Animals increase by orders of magnitude in volume during development. Therefore, small variations in growth rates among individuals could amplify to a large heterogeneity in size. By live imaging of C. elegans, we show that amplification of size heterogeneity is prevented by an inverse coupling of the volume growth rate to the duration of larval stages and does not involve strict size thresholds for larval moulting. We perturb this coupling by changing the developmental tempo through manipulation of a transcriptional oscillator that controls the duration of larval development. As predicted by a mathematical model, this perturbation alters the body volume. Model analysis shows that an inverse relation between the period length and the growth rate is an intrinsic property of genetic oscillators and can occur independently of additional complex regulation. This property of genetic oscillators suggests a parsimonious mechanism that counteracts the amplification of size differences among individuals during development.

FGF8-mediated signaling regulates tooth developmental pace during odontogenesis

The developing human and mouse teeth constitute an ideal model system to study the regulatory mechanism underlying organ growth control since their teeth share highly conserved and well-characterized developmental processes, and their developmental tempo varies notably. In the current study, we manipulated heterogenous recombination between human and mouse dental tissues and demonstrated that the dental mesenchyme dominates the tooth developmental tempo and FGF8 could be a critical player during this developmental process. Forced activation of FGF8 signaling in the dental mesenchyme of mice promoted cell proliferation, prevented cell apoptosis via p38 and perhaps PI3K-Akt intracellular signaling, and impelled the transition of the cell cycle from G1- to S-phase in the tooth germ, resulting in the slowdown of the tooth developmental pace. Our results provide compelling evidence that extrinsic signals can profoundly affect tooth developmental tempo, and the dental mesenchymal FGF8 could be a pivotal factor in controlling the developmental pace in a non-cell-autonomous manner during mammalian odontogenesis.

Growth, Nutrition and Economy

Twenty-three scientists met at Krobielowice, Poland to discuss the role of growth, nutrition and economy on body size. Contrasting prevailing concepts, re-analyses of studies in Indonesian and Guatemalan school children with high prevalence of stunting failed to provide evidence for an association between nutritional status and body height. Direct effects of parental education on growth that were not transmitted via nutrition were shown in Indian datasets using network analysis and novel statistical methods (St. Nicolas House Analysis) that translate correlation matrices into network graphs. Data on Polish children suggest significant impact of socioeconomic sensitivity on child growth, with no effect of maternal money satisfaction. Height and maturation tempo affect the position of a child among its peers. Correlations also exist between mood disorders and height. Secular changes in height and weight varied across decades independent of population size. Historic and recent Russian data showed that height of persons whose fathers performed manual work were on average four cm shorter than persons whose fathers were high-degree specialists. Body height, menarcheal age, and body proportions are sensitive to socioeconomic variables. Additional topics included delayed motherhood and its associations with newborn size; geographic and socioeconomic indicators related to low birth weight, prematurity and stillbirth rate; data on anthropometric history of Brazil, 1850-1950; the impact of central nervous system stimulants on the growth of children with attention-deficit/hyperactivity disorder; and pituitary development and growth hormone secretion. Final discussions debated on reverse causality interfering between social position, and adolescent growth and developmental tempo.

Data-Theoretical Synthesis of the Early Developmental Process.

Biological development is often described as a dynamic, emergent process. This is evident across a variety of phenomena, from the temporal organization of cell types in the embryo to compounding trends that affect large-scale differentiation. To better understand this, we propose combining quantitative investigations of biological development with theory-building techniques. This provides an alternative to the gene-centric view of development: namely, the view that developmental genes and their expression determine the complexity of the developmental phenotype. Using the model system Caenorhabditis elegans, we examine time-dependent properties of the embryonic phenotype and utilize the unique life-history properties to demonstrate how these emergent properties can be linked together by data analysis and theory-building. We also focus on embryogenetic differentiation processes, and how terminally-differentiated cells contribute to structure and function of the adult phenotype. Examining embryogenetic dynamics from 200 to 400min post-fertilization provides basic quantitative information on developmental tempo and process. To summarize, theory construction techniques are summarized and proposed as a way to rigorously interpret our data. Our proposed approach to a formal data representation that can provide critical links across life-history, anatomy and function.

Trends in growth and developmental tempo in boys aged 7 to 18 years between 1966 and 2012 in Poland.

To assess trends in growth in different developmental periods and trends in developmental tempo in Polish boys between 1966 and 2012. Data on 34 828 boys aged 7 to 18 years were collected during Polish Anthropological Surveys conducted in 1966, 1978, 1988, and 2012. Biological parameters, related to onset of adolescent growth spurt (OGS) and peak height velocity (PHV), were derived from a Preece-Baines 1 model (PB1). Childhood (height at 7 years of age), pre-adolescent (height at OGS) and adolescent growth (adult height minus height at OGS) were identified. Positive secular trend between 1966 and 2012 in adult height accounted for, on average, 1.5cm/decade, with varying intensity between the Surveys. Decline in both age at OGS and APHV between 1966 and 2012 (1.5 and 1.4 years, respectively) indicated an acceleration in developmental tempo, on average, by 0.3year/decade. Increases in the contribution to the trend in adult height gained during growth in particular developmental periods between 1966 and 2012 were as followed-childhood: 0.6%, pre-adolescent growth: -3.1%, adolescent growth: 3.1%. Secular trend in developmental tempo and growth among boys reflects changes in living conditions and socio-political aspirations in Poland during nearly 50 years. Acceleration in tempo is already visible at age at OGS, whereas the trend in adult height occurs largely during adolescence, pointing to different regulation of developmental tempo and growth in body height. This finding emphasizes the importance of extending public health intervention into children's growth up until adolescence.

Species-specific segmentation clock periods are due to differential biochemical reaction speeds

Although mechanisms of embryonic development are similar between mice and humans, the time scale is generally slower in humans. To investigate these interspecies differences in development, we recapitulate murine and human segmentation clocks that display 2- to 3-hour and 5- to 6-hour oscillation periods, respectively. Our interspecies genome-swapping analyses indicate that the period difference is not due to sequence differences in the HES7 locus, the core gene of the segmentation clock. Instead, we demonstrate that multiple biochemical reactions of HES7, including the degradation and expression delays, are slower in human cells than they are in mouse cells. With the measured biochemical parameters, our mathematical model accounts for the two- to threefold period difference between the species. We propose that cell-autonomous differences in biochemical reaction speeds underlie temporal differences in development between species.

Indicators of nutritional status and physical activity level as factors associated with the onset of menarche of ten year old girls from Zadar county, Croatia.

The aim is to determine the differences in nutritional status and level of physical activity (PA) of ten year old menstruating and non-menstruating girls. On the sample of 208 girls, fourth graders of elementary schools in Croatia, the indicators of nutritional status were measured: body mass index(BMI), body fat % and waist to hip ratio(WHR), while the PA was assessed using PAQ-C questionnaire. Welch´s t-test was applied to establish the differences and multivariate regression analysis was applied to establish the relationships. Menstruating girls have significantly higher body mass (43.42kg±8.31 vs. 38.64kg±8.33), waist circumference (68.10cm±9.86 vs. 62.22cm±7.16), hip circumference (80.81cm±7.24 vs. 76.63cm±7.7), BMI (19.70±3.42 vs. 17.74±3.10), body fat % (28.05±7.54 vs. 21.98±7.67) and WHR (0.84±0.06 vs. 0.81±0.05) in comparison to non-menstruating girls, while non-menstruating girls have significantly higher PA level (2.93±0.57 vs. 2.68±0.57). The regression analysis have shown a significant relationship between body fat % and the onset of menarche (β=-0.23, SEβ=0.07, p<0.01). Results show differences in the indicators of nutritional status of girls with regard to the status of maturity. Increased nutritional status and body fat % may be indicators of the accelerated developmental tempo and a determinant for the earlier onset of menarche.

The Role of Somatic Maturation on Bioimpedance Patterns and Body Composition in Male Elite Youth Soccer Players.

The purpose of this study was to examine the influence of chronological age (CA) and somatic maturation on body composition (BC) and bioimpedance parameters in male elite soccer players. BC and bioimpedance variables were measured in a sample of 249 players aged 9−18 years of age and registered in two professional Italian soccer teams. Results from segmental analysis showed transition time points where the influence of CA and somatic maturation on bioimpedance patterns and BC characteristics increased or subsided. The accelerated phases were assessed for fat free mass, total body water, and upper muscle area, with a starting time point at approximately −2.00 years from peak at velocity (YPHV), and for body cell mass, whose developmental tempo sped up around −1.00 YPHV. An increase in the rate of development was also observed close to −2.00 YPHV for phase angle (PA), although without accelerated phases. From a CA point of view, significant slope changes were found for all BC and bioimpendance variables, except for the calf muscle area. Although the starting points and the span of the accelerated phases were different, they subsided or disappeared at ~ 15 years, except for PA, whose growth waned at ~ 17 years.

Repressive Gene Regulation Synchronizes Development with Cellular Metabolism

Metabolic conditions affect the developmental tempo of animals. Developmental gene regulatory networks (GRNs) must therefore synchronize their dynamics with a variable timescale. We find that layered repression of genes couples GRN output with variable metabolism. When repressors of transcription or mRNA and protein stability are lost, fewer errors in Drosophila development occur when metabolism is lowered. We demonstrate the universality of this phenomenon by eliminating the entire microRNA family of repressors and find that development to maturity can be largely rescued when metabolism is reduced. Using a mathematical model that replicates GRN dynamics, we find that lowering metabolism suppresses the emergence of developmental errors by curtailing the influence of auxiliary repressors on GRN output. We experimentally show that gene expression dynamics are less affected by loss of repressors when metabolism is reduced. Thus, layered repression provides robustness through error suppression and may provide an evolutionary route to a shorter reproductive cycle.

BAYESIAN ANALYSIS OF INFANT'S GROWTH DYNAMICS WITH IN UTERO EXPOSURE TO ENVIRONMENTAL TOXICANTS.

Early infancy from at-birth to 3 years is critical for cognitive, emotional and social development of infants. During this period, infant's developmental tempo and outcomes are potentially impacted by in utero exposure to endocrine disrupting compounds (EDCs), such as bisphenol A (BPA) and phthalates. We investigate effects of ten ubiquitous EDCs on the infant growth dynamics of body mass index (BMI) in a birth cohort study.Modeling growth acceleration is proposed to understand the "force of growth" through a class of semiparametric stochastic velocity models. The great flexibility of such a dynamic model enables us to capture subject-specific dynamics of growth trajectories and to assess effects of the EDCs on potential delay of growth. We adopted a Bayesian method with the Ornstein-Uhlenbeck process as the prior for the growth rate function, in which the World Health Organization global infant's growth curves were integrated into our analysis. We found that BPA and most of phthalates exposed during the first trimester of pregnancy were inversely associated with BMI growth acceleration, resulting in a delayed achievement of infant BMI peak. Such early growth deficiency has been reported as a profound impact on health outcomes in puberty (e.g., timing of sexual maturation) and adulthood.

Childhood ecology influences salivary testosterone, pubertal age and stature of Bangladeshi UK migrant men.

Male reproductive investment is energetically costly, and measures of human reproductive steroid hormones (testosterone), developmental tempo (pubertal timing) and growth (stature) correlate with local ecologies at the population level. It is unclear whether male reproductive investment in later life is 'set' during childhood development, mediated through adulthood, or varies by ethnicity. Applying a life-course model to Bangladeshi migrants to the United Kingdom, here we investigate plasticity in human male reproductive function resulting from childhood developmental conditions. We hypothesized that childhood ecology shapes adult trade-offs between reproductive investment and/or other fitness-related traits. We predicted correspondence between these traits and developmental timing of exposure to ecological constraints (Bangladesh) or conditions of surplus (United Kingdom). We compared: Bangladesh sedentees (n = 107); Bangladeshi men who migrated in childhood to the United Kingdom (n = 59); migrants who arrived in adulthood (n = 75); second-generation UK-born and raised children of Bangladeshi migrants (n = 56); and UK-born ethnic Europeans (n = 62). Migration before puberty predicted higher testosterone and an earlier recalled pubertal age compared with Bangladeshi sedentees or adult migrants, with more pronounced differences in men who arrived before the age of eight. Second-generation Bangladeshis were taller, with higher testosterone than sedentees and adult migrants, and higher waking testosterone than Europeans. Age-related testosterone profiles varied by group, declining in UK migrants, increasing in sedentees, and having no significant relationship within UK-born groups. We conclude that male reproductive function apparently remains plastic late into childhood, is independent of Bengali or European ethnicity, and shapes physiological trade-offs later in life.

When does the influence of maturation on anthropometric and physical fitness characteristics increase and subside?

The relationships between maturation and anthropometric and physical performance characteristics are dynamic and often asynchronous; confounding the capability to accurately evaluate performance during adolescence. This study aimed to (i) examine the influence of chronological age (CA) and somatic maturation (YPHV) upon anthropometric and physical performance parameters, and (ii) identify the transition/change time points in these relationships using segmental regression. N=969 soccer players (8-18years of age) completed anthropometric and physical test assessments, including a countermovement jump (CMJ), agility T test, 10 and 20m sprints, and multistage fitness test (MSFT). When modeled against CA and YPHV, results identified time point phases with increased rates of stature (CA-7.5, YPHV-8.6cm/y at 10.7-15.2years or -3.2 to +0.8 YPHV) and body mass gain (CA-7.1, YPHV-7.5kg/y at 11.9-16.1years or -1.6 to +4.0 YPHV), followed by gain reductions. Increased rates of sprint performance development (31%-43% gains) occurred at 11.8-15.8 CA or -1.8 to +1.2 YPHV, with gains subsiding thereafter. CMJ, T test, and MSFT gains appeared relatively linear with no change in developmental rate apparent. Developmental tempos did again, however, subside at circa (CMJ and T test) to post-PHV (MSFT). Based on our sample and analysis, periods of increased developmental rates (stature, mass, sprint) were apparent alongside progressive gains for other physical measures, before all subsided at particular age and maturation time points. Findings highlight dynamic asynchronous development of players, physical attributes, and the need to account for the influence of maturation on athletic performance until post-PHV.