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In the mammalian neocortex, projection neuron types are sequentially generated by the same pool of neural progenitors. How neuron type specification is related to developmental timing remains unclear. To determine whether temporal gene expression in neural progenitors correlates with neuron type specification, we performed single-cell RNA sequencing (scRNA-Seq) analysis of the developing mouse neocortex. We uncovered neuroepithelial cell enriched genes such as Hmga2 and Ccnd1 when compared to radial glial cells (RGCs). RGCs display dynamic gene expression over time; for instance, early RGCs express higher levels of Hes5, and late RGCs show higher expression of Pou3f2. Interestingly, intermediate progenitor cell marker gene Eomes coexpresses temporally with known neuronal identity genes at different developmental stages, though mostly in postmitotic cells. Our results delineate neural progenitor cell diversity in the developing mouse neocortex and support that neuronal identity genes are transcriptionally evident in Eomes-positive cells.

What determines the rate at which a multicellular organism matures is a fundamental question in biology. In plants, the decline of miR156 with age serves as an intrinsic, evolutionarily conserved timer for the juvenile-to-adult phase transition. However, the way in which age regulates miR156 abundance is poorly understood. Here, we show that the rate of decline in miR156 is correlated with developmental age rather than chronological age. Mechanistically, we found that cell division in the apical meristem is a trigger for miR156 decline. The transcriptional activity of MIR156 genes is gradually attenuated by the deposition of the repressive histone mark H3K27me3 along with cell division. Our findings thus provide a plausible explanation of why the maturation program of a multicellular organism is unidirectional and irreversible under normal growth conditions and suggest that cell quiescence is the fountain of youth in plants.

It is essential that correct temporal order of cellular events is maintained during animal development. During postembryonic development, the rate of development depends on external conditions, such as food availability, diet, and temperature. How timing of cellular events is impacted when the rate of development is changed at the organism level is not known. We used a unique time-lapse microscopy approach to simultaneously measure timing of oscillatory gene expression, hypodermal stem cell divisions, and cuticle shedding in individual Caenorhabditis elegans larvae, as they developed from hatching to adulthood. This revealed strong variability in timing between isogenic individuals under the same conditions. However, this variability obeyed “temporal scaling,” meaning that events occurred at the same time when measured relative to the total duration of development in each individual. We also observed pervasive changes in timing when temperature, diet, or genotype were varied, but with larval development divided in “epochs” that differed in how event timing was impacted. Yet, these variations in timing were still explained by temporal scaling when time was rescaled by the duration of the respective epochs in each individual. Surprisingly, timing obeyed temporal scaling even in mutants lacking lin-42/Period, presumed a core regulator of timing of larval development, that exhibited strongly delayed, heterogeneous timing. However, shifting conditions middevelopment perturbed temporal scaling and changed event order in a highly condition-specific manner, indicating that a complex machinery is responsible for temporal scaling under constant conditions.

Background Child maltreatment is a potent risk factor for psychopathology. Although the developmental timing of first exposure to maltreatment is considered important in shaping risk of future psychopathology, no consensus exists on whether earlier or later exposures are more deleterious. This study examines whether age at first exposure to abuse is associated with subsequent depression and suicidal ideation. Methods Data were drawn from the National Longitudinal Study of Adolescent Health (n = 15,701). Timing of first maltreatment exposure was classified using: (1) a crude measure capturing early childhood (ages 0–5), middle childhood (ages 6–10), or adolescence (ages 11–17); and (2) a refined measure capturing infancy (ages 0–2), preschool (ages 3–5), latency (ages 6–8), prepubertal (ages 9–10), pubertal (ages 11–13), or adolescence (ages 14–17). We examined whether timing of first exposure was associated with depression and suicidal ideation in early adulthood in the entire sample and among those exposed to maltreatment. Results Respondents exposed to abuse, particularly physical abuse, at any age had a higher odds of depression and suicidal ideation in young adulthood than nonmaltreated respondents. Among maltreated respondents, exposure during early childhood (ages 0–5), particularly preschool (ages 3–5), was most strongly associated with depression. Respondents first exposed to physical abuse during preschool had a 77% increase in the odds of depression and those first exposed to sexual abuse during early childhood had a 146% increase in the odds of suicidal ideation compared to respondents maltreated as adolescents. Conclusions Developmental timing of first exposure to maltreatment influences risk for depression and suicidal ideation. Whether these findings are evidence for biologically based sensitive periods requires further study.

The transition from the juvenile to adult phase in plants is controlled by diverse exogenous and endogenous cues such as age, day length, light, nutrients, and temperature. Previous studies have shown that the gradual decline in microRNA156 (miR156) with age promotes the expression of adult traits. However, how age temporally regulates the abundance of miR156 is poorly understood. We show here that the expression of miR156 responds to sugar. Sugar represses miR156 expression at both the transcriptional level and post-transcriptional level through the degradation of miR156 primary transcripts. Defoliation and photosynthetic mutant assays further demonstrate that sugar from the pre-existing leaves acts as a mobile signal to repress miR156, and subsequently triggers the juvenile-to-adult phase transition in young leaf primordia. We propose that the gradual increase in sugar after seed germination serves as an endogenous cue for developmental timing in plants. Like animals, plants go through several stages of development before they reach maturity, and it has long been thought that some of the transitions between these stages are triggered by changes in the nutritional status of the plant. Now, based on experiments with the plant Arabidopsis thaliana, Yu et al. and, independently, Yang et al. have provided fresh insights into the role of sugar in ‘vegetative phase change'—the transition from the juvenile form of a plant to the adult plant. The new work takes advantage of the fact that vegetative phase change is controlled by two genes that encode microRNAs (MIRNAs). Arabidopsis has eight MIR156 genes and both groups confirmed that supplying plants with sugar reduces the expression of two of these—MIR156A and MIR156C—while sugar deprivation increases their expression. Removing leaves also leads to upregulation of both genes, and delays the juvenile-to-adult transition. Given that this effect can be partially reversed by providing the plant with sugar, it is likely that sugar produced in the leaves—or one of its metabolites—is the signal that triggers the juvenile-to-adult transition through the reduction of miR156 levels. Yu and co-workers confirmed that sugar also reduces the expression of MIR156 in tobacco, moss, and tomato plants, suggesting that this mechanism is evolutionarily conserved. Consistent with the work of Yang and colleagues, Yu and co-workers revealed that sugar is able to reduce the transcription of MIR156A and MIR156C genes into messenger RNA. Moreover, they showed that sugar can also suppress MIR156 expression by promoting the breakdown of MIR156A and MIR156C primary messenger RNA transcripts. The work of Yu et al. and Yang et al. has thus provided key insights into the mechanisms by which a leaf-derived signal controls a key developmental change in plants. Just as fruit flies use their nutritional status to regulate the onset of metamorphosis, and mammals use it to control the onset of puberty, so plants use the level of sugar in their leaves to trigger the transition from juvenile to adult forms.

Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.

In plants, developmental timing is coordinately regulated by a complex signaling network that integrates diverse intrinsic and extrinsic signals. miR172 promotes photoperiodic flowering. It also regulates adult development along with miR156, although the molecular mechanisms underlying this regulation are not fully understood. Here, we demonstrate that miR172 modulates the developmental transitions by regulating the expression of a subset of the SQUAMOSA PROMOTER BINDING PROTEIN - LIKE ( SPL ) genes, which are also regulated by miR156. The SPL3 / 4 / 5 genes were upregulated in the miR172-overproducing plants (35S: 172 ) and its target gene mutants that exhibit early flowering. In contrast, expression of other SPL genes was not altered to a discernible level. Kinetic measurements of miR172 abundance in the transgenic plants expressing the MIR156a gene driven by a β-estradiol-inducible promoter revealed that expressions of miR172 and miR156 are not directly interrelated. Instead, the 2 miRNA signals are integrated at the SPL3 / 4 / 5 genes. Notably, analysis of developmental patterns in the 156 × 172 plants overproducing both miR172 and miR156 showed that whereas vegetative phase change was delayed as observed in the miR156-overproducing plants (35S: 156 ), flowering initiation was accelerated as observed in the 35S: 172 transgenic plants. Together, these observations indicate that although miR172 and miR156 play distinct roles in the timing of developmental phase transitions, there is a signaling crosstalk mediated by the SPL3 / 4 / 5 genes.

Background During the fourth larval (L4) stage, vulval cells of C. elegans undergo extensive morphogenesis accompanied by changes in gene expression. This phase of vulval development, occurring after the well-studied induction of vulval cells, is not well understood but is potentially a useful context in which to study how a complex temporal sequence of events is regulated during development. However, a system for precisely describing different phases of vulval development in the L4 stage has been lacking. Results We defined ten sub-stages of L4 based on morphological criteria as observed using Nomarski microscopy (L4.0 ~ L4.9). Precise timing of each sub-stage at 20 °C was determined. We also re-examined the timing of expression for several gene expression markers, and correlated the sub-stages with the timing of other developmental events in the vulva and the uterus. Conclusions This scheme allows the developmental timing of an L4 individual to be determined at approximately one-hour resolution without the need to resort to time course experiments. These well-defined developmental stages will enable more precise description of gene expression and other developmental events.

During cerebral cortex development, a series of projection neuron types is generated in a fixed temporal order. In Drosophila neuroblasts, the transcription factor hunchback encodes first-born identity within neural lineages. One of its mammalian homologs, Ikaros, was recently reported to play an equivalent role in retinal progenitor cells, raising the question as to whether Ikaros/Hunchback proteins could be general factors regulating the development of early-born fates throughout the nervous system. Ikaros is also expressed in progenitor cells of the mouse cerebral cortex, and this expression is highest during the early stages of neurogenesis and thereafter decreases over time. Transgenic mice with sustained Ikaros expression in cortical progenitor cells and neurons have developmental defects, including displaced progenitor cells within the cortical plate, increased early neural differentiation, and disrupted cortical lamination. Sustained Ikaros expression results in a prolonged period of generation of deep layer neurons into the stages when, normally, only late-born upper layer neurons are generated, as well as a delayed production of late-born neurons. Consequently, more early-born and fewer late-born neurons are present in the cortex of these mice at birth. This phenotype was observed in all parts of the cortex, including those with minimal structural defects, demonstrating that it is not secondary to abnormalities in cortical morphogenesis. These data suggest that Ikaros plays a similar role in regulating early temporal fates in the mammalian cerebral cortex as Ikaros/Hunchback proteins do in the Drosophila nerve cord.

Alterations in the timing of developmental programs during evolution, that lead to changes in the shape, or size of organs, are known as heterochrony. Heterochrony has been widely studied in animals, but has often been neglected in plants. During plant evolution, heterochronic shifts have played a key role in the origin and diversification of leaves, roots, flowers, and fruits. Heterochrony that results in a juvenile or simpler outcome is known as paedomorphosis, while an adult or more complex outcome is called peramorphosis. Mechanisms that alter developmental timing at the cellular level affect cell proliferation or differentiation, while those acting at the tissue or organismal level change endogenous aging pathways, morphogen signaling, and metabolism. We believe that wider consideration of heterochrony in the context of evolution will contribute to a better understanding of plant development.