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PubMed1988

Developmental time course of the effect of nerve growth factor on the parasympathetic ciliary ganglion.

Neurite outgrowth in the presence and absence of nerve growth factor (NGF) was compared in neuronal cultures from the parasympathetic ciliary ganglion and from a traditional target of NGF, the sensory dorsal root ganglion. Both ciliary and dorsal root ganglion cultures exhibited a developmental time window during which the effect of NGF on neurite length was maximal. Although neuronal cultures from embryonic day 4 and 5 ganglia exhibited considerable neurite outgrowth in the absence of NGF, there was no significant increase in neurite outgrowth in the presence of NGF. After embryonic day 6, there was a steady increase in the effect of NGF in both types of ganglia. With ciliary ganglia, the effect of NGF increased until day 8, plateaued, then fell off significantly after day 11. With dorsal root ganglia, the effect of NGF continued to increase until day 12, plateaued, then fell off significantly after day 17. Thus, the period of maximal responsiveness of chick ciliary ganglia to NGF occurs earlier in development than for dorsal root ganglia. At the ages when the effect of NGF was maximal, approximately 20% of ciliary ganglion neurons exhibited substantial increases in neurite length compared to approximately 40% of dorsal root ganglion neurons. The effect of NGF was maximal at or below 1 ng/ml (4 X 10(-11) M) for both types of ganglia. These results support previous evidence that NGF does not simply boost ciliary ganglionic neurite growth non-specifically: the effect of NGF is already maximal at low, physiological concentrations and it appears at a specific time in development.

Animals↗
PubMed2005

Rates of protein evolution are positively correlated with developmental timing of expression during mouse spermatogenesis.

Male reproductive genes often evolve very rapidly, and sexual selection is thought to be a primary force driving this divergence. We investigated the molecular evolution of 987 genes expressed at different times during mouse spermatogenesis to determine if the rate of evolution and the intensity of positive selection vary across stages of male gamete development. Using mouse-rat orthologs, we found that rates of protein evolution were positively correlated with the developmental timing of expression. Genes expressed early in spermatogenesis had rates of divergence similar to the genome median, while genes expressed after the onset of meiosis were found to evolve much more quickly. Rates of protein evolution were fastest for genes expressed during the dramatic morphogenesis of round spermatids into spermatozoa. Late-expressed genes were also more likely to be specific to the male germline. To test for evidence of positive selection, we analyzed the ratio of nonsynonymous to synonymous changes using a maximum likelihood framework in comparisons among mouse, rat, and human. Many genes showed evidence of positive selection, and most of these genes were expressed late in spermatogenesis and were testis specific. Overall, these data suggest that the intensity of positive selection associated with the evolution of male gametes varies considerably across development and acts primarily on phenotypes that develop late in spermatogenesis.

Animals↗
PubMed1995

Slow and fast muscle fibers are preferentially derived from myoblasts migrating into the chick limb bud at different developmental times.

Avian limb myoblasts originate from somites and migrate into the periphery during limb bud formation. It is not known how these precursors become arranged into a stereotyped pattern of muscles and primary fiber types. We used in vivo surgical transplantation and anatomical analyses of thigh muscle patterns to ask whether myoblasts migrating into the limb bud at different developmental times adopt different fates. When myoblast migration was interrupted by transplanting limb bud tissue to the coelomic cavity of a host embryo early in the migratory period (stages 16-early 17), few thigh muscles were found at stages 30-33. Primordia that were present corresponded to muscles that normally contain a majority of slow myotubes. In limbs transplanted slightly later (stages late 17-18), the only missing muscles were those that normally contain the highest numbers of fast myotubes. Parallel results were obtained in chimeric limbs made by transplanting a quail limb bud to a chick host at different times during the migratory period, an experimental situation in which the limbs were not depleted of muscle precursors or nerves. These findings suggest that the earliest myoblast migrants give rise mainly to slow primary myotubes, the later migrants to fast myotubes. To determine whether the early limb bud environment defines the fate of migrating myoblasts, we assessed fiber type patterns in limbs that developed from young limb bud tissue (stages 15-early 16) transplanted to older hosts (stage 17). A significant depletion of slow myosin-positive profiles was found within slow muscles. Fast muscles were generally normal in size. These results provide in vivo evidence that limb myoblast diversity arises prior to the entry of myoblasts into the limb. We suggest that there is a gradual change in the proportions of myoblasts capable of forming slow and fast fiber types, a change which may begin in the somites or early in the migratory period.

Animals↗
PubMed2004

Developmental timing of activated erbB2 expression plays a critical role in the induction of mammary tumors.

Mammary specific expression of the activated erbB2 in the mammary epithelium has been demonstrated to be a potent inducer of mammary carcinomas in number of different transgenic mouse models. Indeed we have recently shown that mammary epithelial specific activation of erbB2 under the transcriptional control of the endogenous erbB2 promoter is capable of inducing focal mammary tumors after a long latency period. To assess whether the developmental timing of expression of this allele would impact tumor formation we expressed the same erbB2 allele under the endogenous promoter in the germline of mice. Our recent report on these mice has revealed that mice expressing the activated erbB2 allele in the germline did not develop tumors although mice expressing an identical allele specifically in the mammary gland at equal levels developed tumors with a high penetrance. These recent reports are reviewed herein and taken together suggest that the developmental window of expression of a potent oncogene may impact tumorigenesis.

Animals↗
PubMed2005

The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. elegans.

In metazoans, microRNAs (miRNAs) carry out various regulatory functions through association with multiprotein miRNA-induced silencing complexes (miRISCs) that contain Dicer and Argonaute proteins. How miRNAs regulate the expression of their mRNA targets remains a major research question. We have identified the C. elegans ain-1 gene through a genetic suppressor screen and shown that it functions with the heterochronic genetic pathway that regulates developmental timing. Biochemical analysis indicates that AIN-1 interacts with protein complexes containing an Argonaute protein, Dicer, and miRNAs. AIN-1 shares homology with the candidate human neurological disease protein GW182, shown to localize in cytoplasmic processing bodies that are sites of mRNA degradation and storage. A functional AIN-1::GFP also localizes at the likely worm processing bodies. When coexpressed from transgenes, AIN-1 targets ALG-1 to the foci. These results suggest a model where AIN-1 regulates a subset of miRISCs by localization to the processing bodies, facilitating degradation or translational inhibition of mRNA targets.

Animals↗
PubMed2005

A developmental timing microRNA and its target regulate life span in C. elegans.

The microRNA lin-4 and its target, the putative transcription factor lin-14, control the timing of larval development in Caenorhabditis elegans. Here, we report that lin-4 and lin-14 also regulate life span in the adult. Reducing the activity of lin-4 shortened life span and accelerated tissue aging, whereas overexpressing lin-4 or reducing the activity of lin-14 extended life span. Lifespan extension conferred by a reduction in lin-14 was dependent on the DAF-16 and HSF-1 transcription factors, suggesting that the lin-4-lin-14 pair affects life span through the insulin/insulin-like growth factor-1 pathway. This work reveals a role for microRNAs and developmental timing genes in life-span regulation.

Aging↗
PubMed1994

Developmentally timed expression of an embryonic growth phenotype in vascular smooth muscle cells.

Little is known about the phenotypic changes that occur in vascular smooth muscle cells (SMCs) as the developing aorta undergoes the transition from a loosely organized, highly replicative tissue to a morphologically mature, quiescent tissue. In the present study, we have characterized the in vivo pattern of SMC replication during intrauterine and neonatal aortic development in the rat and have cultured and assessed the in vitro growth properties of embryonic, fetal, and neonatal vascular SMCs. Embryonic SMCs, which exhibited a very high in vivo replication rate (75% to 80% per day), demonstrated a significant potential for self-driven replication, as assessed by the ability to proliferate under serum-deprived conditions. Several lines of evidence suggest that the autonomous growth of SMCs in the "embryonic growth phenotype" may be driven by a unique mechanism independent of known adult SMC mitogens: embryonic SMC replication was not associated with the detectable secretion of mitogenic activity capable of stimulating adult SMCs, and embryonic SMCs were mitogenically unresponsive to a variety of known adult SMC growth factors. The capacity for self-driven growth was lost by embryonic day 20, suggesting that important changes in gene expression and phenotype occur in developing SMCs between embryonic days 18 and 20. Taken together, the data describe a unique embryonic growth phenotype of vascular SMCs and suggest that the replication of aortic SMCs during intrauterine development is self driven, self regulated, and controlled by a developmental timing mechanism. The conversion of SMCs from the embryonic to the late fetal/adult growth phenotype will likely be found to be an important component of a developmental system controlling vascular morphogenesis.

Animals↗
PubMed2000

Egg timers: how is developmental time measured in the early vertebrate embryo?

Eggs and early embryos appear to be programmed to undertake particular developmental decisions at characteristic times, although precisely how these decisions are timed is unknown. We discuss the possible roles and interactions during early vertebrate development of two broad categories of timers: 1) those that involve cyclic or sequential mechanisms, referred to as clocks; and 2) those that require an increase or decrease in some factor to a threshold level for progression of time, referred to as hourglass timers. It is concluded that both clock-like timers linked to various features of the cell cycle and hourglass timers are involved in early developmental timing. The possible involvement of elements of circadian clock timers is also considered. BioEssays 22:57-63, 2000.

Animals↗
PubMed2006

Regulation of AUXIN RESPONSE FACTOR3 by TAS3 ta-siRNA affects developmental timing and patterning in Arabidopsis.

MicroRNAs (miRNAs) and trans-acting siRNAs (ta-siRNAs) in plants form through distinct pathways, although they function as negative regulators of mRNA targets by similar mechanisms . Three ta-siRNA gene families (TAS1, TAS2, and TAS3) are known in Arabidopsis thaliana. Biogenesis of TAS3 ta-siRNAs, which target mRNAs encoding several AUXIN RESPONSE FACTORs (including ARF3/ETTIN and ARF4 ) involves miR390-guided processing of primary transcripts, conversion of a precursor to dsRNA through RNA-DEPENDENT RNA POLYMERASE6 (RDR6) activity, and sequential DICER-LIKE4 (DCL4)-mediated cleavage events. We show that the juvenile-to-adult phase transition is normally suppressed by TAS3 ta-siRNAs, in an ARGONAUTE7-dependent manner, through negative regulation of ARF3 mRNA. Expression of a nontargeted ARF3 mutant (ARF3mut) in a wild-type background reproduced the phase-change phenotypes detected in rdr6-15 and dcl4-2 mutants, which lose all ta-siRNAs. Expression of either ARF3 or ARF3mut in rdr6-15 plants, in which both endogenous and transgenic copies of ARF3 were derepressed, resulted in further acceleration of phase change and severe morphological and patterning defects of leaves and floral organs. In light of the functions of ARF3 and ARF4 in organ asymmetry, these data reveal multiple roles for TAS3 ta-siRNA-mediated regulation of ARF genes in developmental timing and patterning.

Arabidopsis↗
PubMed2025

Developmental timing of index trauma exposure and accelerated epigenetic aging in United States military veterans.

Trauma exposure has been linked to accelerated GrimAge, an epigenetic biomarker of premature morbidity and mortality. Building on this evidence, the present study examined whether the type and timing of index trauma exposure are differentially associated with accelerated GrimAge. Participants were 873 European American male United States military Veterans from the National Health and Resilience in Veterans Study. We investigated associations between self-reported age at index trauma, index trauma type (interpersonal violence, non-interpersonal trauma, or loss/instability/other), and accelerated GrimAge, operationalized as GrimAge exceeding chronological age by five or more years. Results revealed that interpersonal violence was associated with three-fold greater odds of accelerated GrimAge compared to other trauma types. Age at index trauma was not independently associated with accelerated GrimAge. However, we observed a significant interaction between trauma type and its developmental timing, even after adjusting for index trauma recency, cumulative trauma burden, and other potential confounders. Specifically, Veterans who were older at the time of exposure to interpersonal violence or trauma involving loss or instability had higher odds of accelerated GrimAge. In contrast, exposure to non-interpersonal trauma was more strongly associated with accelerated GrimAge when it occurred at younger ages. These results indicate that trauma type and timing jointly influence epigenetic aging in Veterans, highlighting the need for tailored interventions that address specific trauma characteristics to reduce associated long-term health risks in this population.

Humans↗
PubMed1985

Deletions within a defective suppressor-mutator element in maize affect the frequency and developmental timing of its excision from the bronze locus.

Six independent derivatives of the bz-m13 allele, which contains a 2.2-kilobase-pair defective Suppressor-mutator (dSpm) insertion at the bronze (bz) locus, have been isolated and analyzed. The derivatives were selected for alterations in the frequency and timing of somatic reversion; such derivatives have previously been analyzed genetically and designated "changes in state" by McClintock [McClintock, B. (1955) Carnegie Inst. Washington, Yearb. 54, 245-255]. All of the derivatives analyzed in the present study revert substantially later in development than the original insertion mutation and some show a very low frequency of reversion as well. All of the derivatives contain insertions at the same site as the parent bz-m13 allele. Deletions of 400-1300 base pairs were found in the dSpm elements in four of the six derivatives; the remaining derivatives could not be distinguished structurally from the original mutant allele. The results suggest that changes in the frequency and developmental timing of excision are attributable to alterations in the dSpm element. Furthermore, these data suggest that DNA sequences near the ends of the element are important for responding to the two transacting functions supplied by the transposition-competent Suppressor-mutator (Spm) element.

Base Sequence↗
PubMed1998

Alcohol-induced Purkinje cell loss depends on developmental timing of alcohol exposure and correlates with motor performance.

Several reports indicate that neonatal ethanol exposure induces cerebellar Purkinje and granule cell loss if exposure occurs before postnatal day (PD) 7, and that cerebellar damage may underlie ethanol-induced motor deficits. The present study used an unbiased stereological method, the optical fractionator, to count total cerebellar Purkinje cell number in groups of Sprague-Dawley rats given binge-like ethanol exposure at different neonatal ages. Correlations between Purkinje cell number (of 55-day-old rats) and parallel bar motor performance (previously tested on PD 30-32) were also evaluated. One group was given binge-like exposure to 6.6 g/kg per day of ethanol via artificial rearing on PD 4 and 5 (PD 4/5); a second group on PD 8 and 9 (PD 8/9); and a third group on both PD 4 and 5 and 8 and 9 (Comb). Gastrostomy (CG) and suckle (SC) control groups were also included. Purkinje cells were significantly reduced in all three ethanol-treated groups compared to controls, but the severity of loss was significantly greater in the PD 4/5 and Comb groups (reduced by 42% and 45%, respectively, relative to GC) compared to the PD 8/9 group (reduced by 15%). Across treatment groups, the total cerebellar Purkinje cell number was significantly correlated with successful parallel bar traversal (r = +0.74), supporting the contention that ethanol-induced motor deficits may be associated with cerebellar cell loss. These data confirm the presence of windows of vulnerability of Purkinje cells to neurotoxic effects of binge ethanol treatment, and demonstrate that both the behavioral and neuroanatomical consequences of binge exposure depend on the developmental timing of the exposure.

Aging↗
PubMed2003

The Caenorhabditis elegans hunchback-like gene lin-57/hbl-1 controls developmental time and is regulated by microRNAs.

Temporal control of development is an important aspect of pattern formation that awaits complete molecular analysis. We identified lin-57 as a member of the C. elegans heterochronic gene pathway, which ensures that postembryonic developmental events are appropriately timed. Loss of lin-57 function causes the hypodermis to terminally differentiate and acquire adult character prematurely. lin-57 is hbl-1, revealing a role for the worm hunchback homolog in control of developmental time. Significantly, fly hunchback (hb) temporally specifies cell fates in the nervous system. The hbl-1/lin-57 3'UTR is required for postembryonic downregulation in the hypodermis and nervous system and contains multiple putative binding sites for temporally regulated microRNAs, including let-7. Indeed, we find that hbl-1/lin-57 is regulated by let-7, at least in the nervous system. Examination of the hb 3'UTR reveals potential binding sites for known fly miRNAs. Thus, evolutionary conservation of hunchback genes may include temporal control of cell fate specification and microRNA-mediated regulation.

3' Untranslated Regions↗
PubMed1992

Maize mutants and variants altering developmental time and their heterochronic interactions.

It is useful to envision two fundamentally different ways by which the timing of plant development is regulated: developmental stage-transition mechanisms and time-to-flowering mechanisms. The existence of both mechanisms is indicated by the behavior of various mutants. Shoot stage transitions are defined by dominant mutants representing at least four different genes; each mutant retards transitions from juvenile shoot stages to more adult shoot stages. In addition, dominant leaf stage-transition mutants in at least seven different genes have similar phenotypes, but the leaf rather than the shoot is the focus (and at least two of these genes encode homeodomain proteins.) One mutant, Hairy sheath frayed 1-O (Hsf1-O) simultaneously affects shoot and leaf; this mutant's behavior initiated our interest in plant heterochronism. The second type of timekeeping involves time-to-flowering. As with most plant but not animal species, cultivars of the maize species vary greatly for the time-to-flowering quantitative trait: between 6 and 14 weeks is common. It is via the 'slipping time frames' interaction that takes place between stage-transition mutants and time-to-flowering genetic backgrounds that unexpected and radical phenotypes occur. We see a reservoir of previously unsuspected morphological possibilities among the few heterochronic genotypes we have constructed, possibilities that may mimic the sort of variation needed to fuel macroevolution without having to posit (as done by Goldschmidt) any special macromutational mechanisms.

Biological Evolution↗
PubMed1984

Developmental time, cell lineage, and environment regulate the newly synthesized proteins in sea urchin embryos.

Strongylocentrotus purpuratus embryos were fractionated into two cell populations of defined lineages at times corresponding to two critical developmental events: determination (16-cell stage) and early differentiation (mesenchyme blastula). The 16-cell stage blastomeres, labeled with [35S]methionine, exhibited identical protein synthesis patterns by fluorography, and this pattern was not significantly altered by cell separation. In comparing the proteins of the mesenchyme blastula to the 16-cell stage, differences (increases and decreases) were seen by fluorography of newly synthesized proteins. The synthesis of 2.9% of the mesenchyme blastula proteins is specific to or enriched in primary mesenchyme cells and 8.2% is specific to or enriched in endoderm/ectoderm cells. Additionally, in contrast to the earlier stage, the pattern of protein synthesis in the mesenchyme blastula embryos is substantially altered by cell separation. The ability to alter protein synthesis in response to environmental factors may be a further demonstration of the differentiation of these cells.

Animals↗
PubMed1983

An analysis of developmental timing in Dictyostelium discoideum.

A new method has been developed to assess the minimum complexity and relationships of those pathways (developmental timers) which time the consecutive stages of a developing system (Soll, 1983). This method has been applied to the morphogenetic program of Dictyostelium discoideum and has resulted in (1) a minimum estimate of the number of components comprising the timers for the first seven stages of morphogenesis, (2) a characterization of the temperature sensitivities of these components including demonstration of a reversible timer component, (3) detained temporal definition of a number of transition points between rate-limiting components including a major branch point for the onset of several independent timer components coincident with the onset of aggregation, and (4) a temporal model for the relationships between the timers of the seven consecutive morphogenetic stages, including several examples of parallel timers.

Biological Clocks↗
PubMed2005

Polycomb group genes control developmental timing of endosperm.

Polycomb (PcG) group proteins form modular complexes, which maintain repressed transcriptional states of target genes across cell divisions. As PcG complexes provide a memory of cell fate, such proteins might control temporal aspects of development. Loss-of-function of any of the FERTILIZATION INDEPENDENT SEED (FIS) PcG genes perturbs endosperm development. In this report we provide a detailed analysis of the phenotype of fis endosperm development using molecular and cellular markers. Wild type (WT) endosperm development undergoes a series of four major developmental phases timed by successive synchronous nuclei division. In fis endosperm the transition from phase 1, marked by a synchronous mode of nuclei divisions to phase 2, corresponding to the establishment of three mitotic domains, is absent. Accordingly, the expression of seven markers of phase 1 and phase 2 is temporally perturbed. In spite of such changes, specific sequences of developmental events still take place as in the WT. Overall, fis mutations are heterochronic mutations that cause a temporal deregulation in the ontogenic sequence of endosperm development.

Arabidopsis↗
PubMed2005

The Caenorhabditis elegans heterochronic regulator LIN-14 is a novel transcription factor that controls the developmental timing of transcription from the insulin/insulin-like growth factor gene ins-33 by direct DNA binding.

A temporal gradient of the novel nuclear protein LIN-14 specifies the timing and sequence of stage-specific developmental events in Caenorhabditis elegans. The profound effects of lin-14 mutations on worm development suggest that LIN-14 directly or indirectly regulates stage-specific gene expression. We show that LIN-14 can associate with chromatin in vivo and has in vitro DNA binding activity. A bacterially expressed C-terminal domain of LIN-14 was used to select DNA sequences that contain a putative consensus binding site from a pool of randomized double-stranded oligonucleotides. To identify candidates for genes directly regulated by lin-14, we employed DNA microarray hybridization to compare the mRNA abundance of C. elegans genes in wild-type animals to that in mutants with reduced or elevated lin-14 activity. Five of the candidate LIN-14 target genes identified by microarrays, including the insulin/insulin-like growth factor family gene ins-33, contain putative LIN-14 consensus sites in their upstream DNA sequences. Genetic analysis indicates that the developmental regulation of ins-33 mRNA involves the stage-specific repression of ins-33 transcription by LIN-14 via sequence-specific DNA binding. These results reinforce the conclusion that lin-14 encodes a novel class of transcription factor.

Animals↗