Long-Term Programming of CD8 T Cell Immunity by Perinatal Exposure to Glucocorticoids.

Early life environmental exposure, particularly during perinatal period, can have a life-long impact on organismal development and physiology. The biological rationale for this phenomenon is to promote physiological adaptations to the anticipated environment based on early life experience. However, perinatal exposure to adverse environments can also be associated with adult-onset disorders. Multiple environmental stressors induce glucocorticoids, which prompted us to investigate their role in developmental programming. Here, we report that perinatal glucocorticoid exposure had long-term consequences and resulted in diminished CD8 T cell response in adulthood and impaired control of tumor growth and bacterial infection. We found that perinatal glucocorticoid exposure resulted in persistent alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Consequently, the level of the hormone in adults was significantly reduced, resulting in decreased CD8 T cell function. Our study thus demonstrates that perinatal stress can have long-term consequences on CD8 T cell immunity by altering HPA axis activity.

Genetics of Shoot Meristem and Shoot Regeneration.

Plants exhibit remarkable lineage plasticity, allowing them to regenerate organs that differ from their respective origins. Such developmental plasticity is dependent on the activity of pluripotent founder cells or stem cells residing in meristems. At the shoot apical meristem (SAM), the constant flow of cells requires continuing cell specification governed by a complex genetic network, with the WUSCHEL transcription factor and phytohormone cytokinin at its core. In this review, I discuss some intriguing recent discoveries that expose new principles and mechanisms of patterning and cell specification acting both at the SAM and prior to meristem organogenesis during shoot regeneration. I also highlight unanswered questions and future challenges in the study of SAM and meristem regeneration. Finally, I put forward a model describing stochastic events mediated by epigenetic factors to explain how the gene regulatory network might be initiated at the onset of shoot regeneration.

Neuronal Development of Hearing and Language: Cochlear Implants and Critical Periods.

The modern cochlear implant (CI) is the most successful neural prosthesis developed to date. CIs provide hearing to the profoundly hearing impaired and allow the acquisition of spoken language in children born deaf. Results from studies enabled by the CI have provided new insights into (a) minimal representations at the periphery for speech reception, (b) brain mechanisms for decoding speech presented in quiet and in acoustically adverse conditions, (c) the developmental neuroscience of language and hearing, and (d) the mechanisms and time courses of intramodal and cross-modal plasticity. Additionally, the results have underscored the interconnectedness of brain functions and the importance of top-down processes in perception and learning. The findings are described in this review with emphasis on the developing brain and the acquisition of hearing and spoken language.

Assessment and the regulation of adaptive phenotypic plasticity.

Organisms can react to environmental variation by altering their phenotype, and such phenotypic plasticity is often adaptive. This plasticity contributes to the diversity of phenotypes across the tree of life. Generally, the production of these phenotypes must be preceded by assessment, where the individual acquires information about its environment and phenotype relative to that environment, and then determines if and how to respond with an alternative phenotype. The role of assessment in adaptive plasticity is, therefore, crucial. In this Review, we (1) highlight the need for explicitly considering the role of assessment in plasticity; (2) present two different models for how assessment and the facultative production of phenotypes are related; and (3) describe an overarching framework for how assessment evolves. In doing so, we articulate avenues of future work and suggest that explicitly considering the role of assessment in the evolution of plasticity is key to explaining how and when plasticity occurs. Moreover, we emphasize the need to understand the role of assessment in adaptive versus maladaptive plasticity, which is an issue that will become increasingly important in a rapidly changing world.

Stomatal development in the changing climate.

Stomata, microscopic pores flanked by symmetrical guard cells, are vital regulators of gas exchange that link plant processes with environmental dynamics. The formation of stomata involves the multi-step progression of a specialized cell lineage. Remarkably, this process is heavily influenced by environmental factors, allowing plants to adjust stomatal production to local conditions. With global warming set to alter our climate at an unprecedented pace, understanding how environmental factors impact stomatal development and plant fitness is becoming increasingly important. In this Review, we focus on the effects of carbon dioxide, high temperature and drought - three environmental factors tightly linked to global warming - on stomatal development. We summarize the stomatal response of a variety of plant species and highlight the existence of species-specific adaptations. Using the model plant Arabidopsis, we also provide an update on the molecular mechanisms involved in mediating the plasticity of stomatal development. Finally, we explore how knowledge on stomatal development is being applied to generate crop varieties with optimized stomatal traits that enhance their resilience against climate change and maintain agricultural productivity.

A predisposed motor bias shapes individuality in vocal learning.

The development of individuality during learned behavior is a common trait observed across animal species; however, the underlying biological mechanisms remain understood. Similar to human speech, songbirds develop individually unique songs with species-specific traits through vocal learning. In this study, we investigate the developmental and molecular mechanisms underlying individuality in vocal learning by utilizing F1 hybrid songbirds (Taeniopygia guttata cross with Taeniopygia bichenovii), taking an integrating approach combining experimentally controlled systematic song tutoring, unbiased discriminant analysis of song features, and single-cell transcriptomics. When tutoring with songs from both parental species, F1 hybrid individuals exhibit evident diversity in their acquired songs. Approximately 30% of F1 hybrids selectively learn either song of the two parental species, while others develop merged songs that combine traits from both species. Vocal acoustic biases during vocal babbling initially appear as individual differences in songs among F1 juveniles and are maintained through the sensitive period of song vocal learning. These vocal acoustic biases emerge independently of the initial auditory experience of hearing the biological father's and passive tutored songs. We identify individual differences in transcriptional signatures in a subset of cell types, including the glutamatergic neurons projecting from the cortical vocal output nucleus to the hypoglossal nuclei, which are associated with variations of vocal acoustic features. These findings suggest that a genetically predisposed vocal motor bias serves as the initial origin of individual variation in vocal learning, influencing learning constraints and preferences.

Nutritional control of developmental processes.

Nutritional and metabolic cues are integral to animal development. Organisms use them both as sustenance and environmental indicators, fueling, informing and influencing developmental decisions. Classical examples, such as the Warburg effect, clearly illustrate how genetic programs control metabolic changes. However, the way that nutrition and metabolism can also modulate or drive genetic programs to instruct developmental trajectories is much more elusive, owing to several difficulties including uncoupling permissive and instructive functions. Here, we discuss recent advancements in the field that highlight the developmental role of nutritional and metabolic cues across multiple levels of organismal complexity.

On developmental programming of the immune system.

Early-life environmental exposures play a significant role in shaping long-lasting immune phenotypes and disease susceptibility. Nevertheless, comprehensive understanding of the developmental programming of immunity is limited. We propose that the vertebrate immune system contains durable programmable components established through early environmental interactions and maintained in a stable and homeostatic manner. Some immune components, such as immunological memory, are intrinsically programmable. Others are influenced by conditions during critical developmental windows in early life, including microbiota, hormones, metabolites, and environmental stress, which impact programming. Developmental immune programming can promote adaptation to an anticipated future environment. However, mismatches between predicted and actual environments can result in disease. This is relevant because understanding programming mechanisms can offer insights into the origin of inflammatory diseases, ideally enabling effective prevention and treatment strategies.

Developmental bias predicts 60 million years of wing shape evolution.

The degree to which developmental biases affect trait evolution is subject to much debate. Here, we first quantify fluctuating asymmetry as a measure of developmental variability, i.e., the propensity of developmental systems to create some phenotypic variants more often than others, and show that it predicts phenotypic and standing genetic variation as well as deep macroevolutionary divergence in wing shape in sepsid flies. Comparing our data to the findings of a previous study demonstrates that developmental variability in the sepsid fly Sepsis punctum strongly aligns with mutational, standing genetic, and macroevolutionary variation in the Drosophilidae--a group that diverged from the sepsid lineage ca. 64 My ago. We also find that developmental bias in S. punctum wing shape aligns with the effects of allometry, but less so with putatively adaptive thermal plasticity and population differentiation along latitude. Our findings demonstrate that developmental bias in fly wings predicts evolvability and macroevolutionary trajectories on a much greater scale than previously appreciated but also suggest that causal explanations for such alignments may go beyond simple constraint hypotheses.

A Mediator subunit imparts robustness to a polyphenism decision.

Polyphenism is a type of developmental plasticity that translates continuous environmental variability into discontinuous phenotypes. Such discontinuity likely requires a switch between alternative gene-regulatory networks, a principle that has been borne out by mechanisms found to promote morph-specific gene expression. However, whether robustness is required to execute a polyphenism decision has awaited testing at the molecular level. Here, we used a nematode model for polyphenism, Pristionchus pacificus, to identify the molecular regulatory factors that ensure the development of alternative forms. This species has a dimorphism in its adult feeding structures, specifically teeth, which are a morphological novelty that allows predation on other nematodes. Through a forward genetic screen, we determined that a duplicate homolog of the Mediator subunit MDT-15/MED15, P. pacificus MDT-15.1, is necessary for the polyphenism and the robustness of the resulting phenotypes. This transcriptional coregulator, which has a conserved role in metabolic responses to nutritional stress, coordinates these processes with its effects on this diet-induced polyphenism. Moreover, this MED15 homolog genetically interacts with two nuclear receptors, NHR-1 and NHR-40, to achieve dimorphism: Single and double mutants for these three factors result in morphologies that together produce a continuum of forms between the extremes of the polyphenism. In summary, we have identified a molecular regulator that confers discontinuity to a morphological polyphenism, while also identifying a role for MED15 as a plasticity effector.

A theoretical perspective on Waddington's genetic assimilation experiments.

Genetic assimilation is the process by which a phenotype that is initially induced by an environmental stimulus becomes stably inherited in the absence of the stimulus after a few generations of selection. While the concept has attracted much debate after being introduced by C. H. Waddington 70 y ago, there have been few experiments to quantitatively characterize the phenomenon. Here, we revisit and organize the results of Waddington's original experiments and follow-up studies that attempted to replicate his results. We then present a theoretical model to illustrate the process of genetic assimilation and highlight several aspects that we think require further quantitative studies, including the gradual increase of penetrance, the statistics of delay in assimilation, and the frequency of unviability during selection. Our model captures Waddington's picture of developmental paths in a canalized landscape using a stochastic dynamical system with alternative trajectories that can be controlled by either external signals or internal variables. It also reconciles two descriptions of the phenomenon-Waddington's, expressed in terms of an individual organism's developmental paths, and that of Bateman in terms of the population distribution crossing a hypothetical threshold. Our results provide theoretical insight into the concepts of canalization, phenotypic plasticity, and genetic assimilation.

Enhancer, transcriptional, and cell fate plasticity precedes intestinal determination during endoderm development.

After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro-caudal patterning and transcription factor (TF)-dependent interim plasticity. Foregut-specific enhancers are as accessible and active in early midgut as in foregut endoderm, and intestinal enhancers and identity are established only after ectopic cis-regulatory elements are decommissioned. Depletion of the intestinal TF CDX2 before this cis element transition stabilizes foregut enhancers, reinforces ectopic transcriptional programs, and hence imposes foregut identities on the midgut. Later in development, as the window of chromatin plasticity elapses, CDX2 depletion weakens intestinal, without strengthening foregut, enhancers. Thus, midgut endoderm is primed for heterologous cell fates, and TFs act on a background of shifting chromatin access to determine intestinal at the expense of foregut identity. Similar principles likely govern other fate commitments.

Deep conservation and co-option of programmed cell death facilitates evolution of alternative phenotypes at multiple biological levels.

Alternative phenotypes, such as polyphenisms and sexual dimorphisms, are widespread in nature and appear at all levels of biological organization, from genes and cells to morphology and behavior. Yet, our understanding of the mechanisms through which alternative phenotypes develop and how they evolve remains understudied. In this review, we explore the association between alternative phenotypes and programmed cell death, a mechanism responsible for the elimination of superfluous cells during development. We discuss the ancient origins and deep conservation of programmed cell death (its function, forms and underlying core regulatory gene networks), and propose that it was co-opted repeatedly to generate alternative phenotypes at the level of cells, tissues, organs, external morphology, and even individuals. We review several examples from across the tree of life to explore the conditions under which programmed cell death is likely to facilitate the evolution of alternative phenotypes.

A genetic framework for proximal secondary vein branching in the Arabidopsis thaliana embryo.

Over time, plants have evolved flexible self-organizing patterning mechanisms to adapt tissue functionality for continuous organ growth. An example of this process is the multicellular organization of cells into a vascular network in foliar organs. An important, yet poorly understood component of this process is secondary vein branching, a mechanism employed to extend vascular tissues throughout the cotyledon surface. Here, we uncover two distinct branching mechanisms during embryogenesis by analyzing the discontinuous vein network of the double mutant cotyledon vascular pattern 2 (cvp2) cvp2-like 1 (cvl1). Similar to wild-type embryos, distal veins in cvp2 cvl1 embryos arise from the bifurcation of cell files contained in the midvein, whereas proximal branching is absent in this mutant. Restoration of this process can be achieved by increasing OCTOPUS dosage as well as by silencing RECEPTOR-LIKE PROTEIN KINASE 2 (RPK2) expression. Although RPK2-dependent rescue of cvp2 cvl1 is auxin- and CLE peptide-independent, distal branching involves polar auxin transport and follows a distinct regulatory mechanism. Our work defines a genetic network that confers plasticity to Arabidopsis embryos to spatially adapt vascular tissues to organ growth.

Nutrition-dependent juvenile hormone sensitivity promotes flight-muscle degeneration during the aphid dispersal-reproduction transition.

In insects, the loss of flight typically involves a dispersal-reproduction transition, but the underlying molecular mechanisms remain poorly understood. In the parthenogenetic pea aphid Acyrthosiphon pisum, winged females undergo flight-muscle degeneration after flight and feeding on new host plants. Similarly, topical application of a juvenile hormone (JH) mimic to starved aphids also induces flight-muscle degeneration. We found that feeding preferentially upregulated the expression of the JH receptor gene Met and a JH-inducible gene, Kr-h1, in the flight muscles, and, thus, enhanced tissue-specific JH sensitivity and signaling. RNAi-mediated knockdown of Kr-h1 prevented flight-muscle degeneration. Likewise, blocking nutritional signals by pharmacological inhibition of the target of rapamycin complex 1 (TORC1) impaired JH sensitivity of the flight muscles in feeding aphids and subsequently delayed muscle degeneration. RNA-sequencing analysis revealed that enhanced JH signaling inhibited the transcription of genes involved in the tricarboxylic acid cycle, likely resulting in reduction of the energy supply, mitochondrial dysfunction and muscle-fiber breakdown. This study shows that nutrient-dependent hormone sensitivity regulates developmental plasticity in a tissue-specific manner, emphasizing a relatively underappreciated mechanism of hormone sensitivity in modulating hormone signaling.

Evidence for an adolescent sensitive period to family experiences influencing adult male testosterone production.

Across vertebrates, testosterone is an important mediator of reproductive trade-offs, shaping how energy and time are devoted to parenting versus mating/competition. Based on early environments, organisms often calibrate adult hormone production to adjust reproductive strategies. For example, favorable early nutrition predicts higher adult male testosterone in humans, and animal models show that developmental social environments can affect adult testosterone. In humans, fathers' testosterone often declines with caregiving, yet these patterns vary within and across populations. This may partially trace to early social environments, including caregiving styles and family relationships, which could have formative effects on testosterone production and parenting behaviors. Using data from a multidecade study in the Philippines (n = 966), we tested whether sons' developmental experiences with their fathers predicted their adult testosterone profiles, including after they became fathers themselves. Sons had lower testosterone as parents if their own fathers lived with them and were involved in childcare during adolescence. We also found a contributing role for adolescent father­son relationships: sons had lower waking testosterone, before and after becoming fathers, if they credited their own fathers with their upbringing and resided with them as adolescents. These findings were not accounted for by the sons' own parenting and partnering behaviors, which could influence their testosterone. These effects were limited to adolescence: sons' infancy or childhood experiences did not predict their testosterone as fathers. Our findings link adolescent family experiences to adult testosterone, pointing to a potential pathway related to the intergenerational transmission of biological and behavioral components of reproductive strategies.

Language and developmental plasticity after perinatal stroke.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

WUSCHEL-related homeobox family genes in rice control lateral root primordium size.

The development of a plastic root system is essential for stable crop production under variable environments. Rice plants have two types of lateral roots (LRs): S-type (short and thin) and L-type (long, thick, and capable of further branching). LR types are determined at the primordium stage, with a larger primordium size in L-types than S-types. Despite the importance of LR types for rice adaptability to variable water conditions, molecular mechanisms underlying the primordium size control of LRs are unknown. Here, we show that two WUSCHEL-related homeobox (WOX) genes have opposing roles in controlling LR primordium (LRP) size in rice. Root tip excision on seminal roots induced L-type LR formation with wider primordia formed from an early developmental stage. QHB/OsWOX5 was isolated as a causative gene of a mutant that is defective in S-type LR formation but produces more L-type LRs than wild-type (WT) plants following root tip excision. A transcriptome analysis revealed that OsWOX10 is highly up-regulated in L-type LRPs. OsWOX10 overexpression in LRPs increased the LR diameter in an expression-dependent manner. Conversely, the mutation in OsWOX10 decreased the L-type LR diameter under mild drought conditions. The qhb mutants had higher OsWOX10 expression than WT after root tip excision. A yeast one-hybrid assay revealed that the transcriptional repressive activity of QHB was lost in qhb mutants. An electrophoresis mobility shift assay revealed that OsWOX10 is a potential target of QHB. These data suggest that QHB represses LR diameter increase, repressing OsWOX10 Our findings could help improve root system plasticity under variable environments.

Cumulative adversity and survival in the wild.

Protecting populations contending with co-occurring stressors requires a better understanding of how multiple early-life stressors affect the fitness of natural systems. However, the complexity of such research has limited its advancement and prevented us from answering new questions. In human studies, cumulative risk models predict adult health risk based on early adversity exposure. We apply a similar framework in wild yellow-bellied marmots (Marmota flaviventer). We tested cumulative adversity indices (CAIs) across different adversity types and time windows. All CAIs were associated with decreased pup survival and were well supported. Moderate and acute, but not standardized CAIs were associated with decreased lifespan, supporting the cumulative stress hypothesis and the endurance of early adversity. Multivariate models showed that differences in lifespan were driven by weaning date, precipitation, and maternal loss, but they performed poorly compared with CAI models. We highlight the development, utility, and insights of CAI approaches for ecology and conservation.

Developmental plasticity and variability in the formation of egg-spots, a pigmentation ornament in the cichlid Astatotilapia calliptera.

Vertebrate pigmentation patterns are highly diverse, yet we have a limited understanding of how evolutionary changes to genetic, cellular, and developmental mechanisms generate variation. To address this, we examine the formation of a sexually-selected male ornament exhibiting inter- and intraspecific variation, the egg-spot pattern, consisting of circular yellow-orange markings on the male anal fins of haplochromine cichlid fishes. We focus on Astatotilapia calliptera, the ancestor-type species of the Malawi cichlid adaptive radiation of over 850 species. We identify a key role for iridophores in initializing egg-spot aggregations composed of iridophore-xanthophore associations. Despite adult sexual dimorphism, aggregations initially form in both males and females, with development only diverging between the sexes at later stages. Unexpectedly, we found that the timing of egg-spot initialization is plastic. The earlier individuals are socially isolated, the earlier the aggregations form, with iridophores being the cell type that responds to changes to the social environment. Furthermore, we observe apparent competitive interactions between adjacent egg-spot aggregations, which strongly suggests that egg-spot patterning results mostly from cell-autonomous cellular interactions. Together, these results demonstrate that A. calliptera egg-spot development is an exciting model for investigating pigment pattern formation at the cellular level in a system with developmental plasticity, sexual dimorphism, and intraspecific variation. As A. calliptera represents the ancestral bauplan for egg-spots, these findings provide a baseline for informed comparisons across the incredibly diverse Malawi cichlid radiation.