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PubMed1997

Distal regulatory elements control MRF4 gene expression in early and late myogenic cell populations.

MRF4 is a muscle-specific transcription factor that belongs to a family of basic helix-loop-helix proteins known as the myogenic regulatory factors (MRFs). In vitro studies have shown that expression of the MRF4 gene is controlled by a proximal promoter element (-336 to +71) that binds the muscle-specific transcription factors MEF2 and myogenin to activate transcription. To examine further the regulatory elements necessary for endogenous MRF4 gene expression during development, transgenic mice were generated that contained either a proximal MRF4 promoter-LacZ reporter gene (-336 MRF4-nLacZ) or a MRF4-LacZ reporter gene containing 8.5 kb of 5' flanking sequence (-8500 MRF4-nLacZ). Characterization of individual transgenic mouse lines throughout development revealed that expression of both transgenes is restricted to skeletal muscle tissue. However, unlike previous in vitro data, the proximal promoter transgene exhibits only limited transcriptional activity at all developmental time points, whereas the -8500 MRF4-nLacZ lines fully recapitulate the later developmental expression patterns and exhibit transcription in myotomal cells during somitic differentiation. Tissue culture analysis of myogenic cells isolated from E12.5, E16.5, and adults confirmed that the -8500 MRF4-nLacZ transgene is expressed in greater than 90% of the myotubes for all myogenic populations. These results indicate that 8.5 kb of MRF4 5' flanking sequence contains all the regulatory elements necessary for late MRF4 expression and that at least some of these elements lie upstream of the -336 proximal promoter. It is also likely that distant upstream regulatory sequences control early somitic MRF4 expression. These findings, coupled with previous in vitro studies, suggest that the early and late developmental expression patterns of the MRF4 gene are controlled by distinct sets of regulatory elements.

Animals↗

PubMed1997

Prenatal exposure to disulfiram implicated in the cause of malformations in discordant monozygotic twins.

Female monozygotic (MZ) twins were discordant for congenital structural anomalies: Twin A had a reduction defect of the right forearm; Twin B had a cleft palate. Both infants were small for gestational age. Specific prenatal exposures were identified at different times in the first trimester of pregnancy: crack cocaine, marijuana, disulfiram, heavy ethanol exposure, and cigarettes. The mother's hospitalization in a drug abuse program and incarceration allowed for identification of exposure timing. The cleft palate could have been related to either disulfiram or alcohol exposure; the limb abnormality most likely corresponded to the timing of disulfiram exposure. Discordance of anomalies in these twins may reflect differences in developmental timing, differences in susceptibility to one or more teratogens, or random events occurring within very complex developmental programs, with the thresholds for malformation affected by one or multiple teratogenic compounds.

Abnormalities, Drug-Induced↗

PubMed1991

The ontogeny of the uptake systems for glycine, GABA and glutamate in synaptic vesicles isolated from rat spinal cord-medulla.

Synaptic vesicles have been isolated from rat spinal cord-medulla at different postnatal ages, and the ontogeny of the uptake of glycine, gamma-aminobutyric acid (GABA) and glutamate has been investigated. The accumulation of the 3 amino acids increased with increasing time after birth reaching adult level at about postnatal day 30. This developmental increase probably parallels the synaptogenesis and suggests a functional role of the uptake of the amino acids into synaptic vesicles in the nerve terminals. The developmental time course for these vesicular uptake systems was totally different from those of the corresponding plasma membrane uptakes.

Aging↗

PubMedDate not supplied

Mode of action: developmental thyroid hormone insufficiency--neurological abnormalities resulting from exposure to propylthiouracil.

Because thyroid hormone is essential for normal brain development before and after birth, environmental chemicals that interfere with thyroid hormone signaling can adversely affect brain development. Adverse consequences of thyroid hormone insufficiency depend both on severity and developmental timing, indicating that environmental antithyroid factors may produce different effects at different developmental windows of exposure. Mechanistic studies can provide important insight into the potential impact of chemicals on human thyroid function, but relevance to humans must be systematically evaluated. This kind of analysis depends on data sets that include information about animals and humans. The drug 6-n-propyl-2-thiouracil (PTU) is used in animals to experimentally manipulate serum thyroid hormone levels, and in humans to treat patients, including pregnant women, with Graves' disease. A systematic analysis of the mode of action (MOA) of PTU in rats and in humans discloses similar modes of action. While the analysis predicts that PTU doses that produce thyroid hormone insufficiency in humans would adversely affect the developing brain, careful monitoring of PTU administration in pregnant and lactating humans keeps infant serum thyroid hormone levels within the normal range.

Abnormalities, Drug-Induced↗

PubMed2006

Programmed cell death mechanisms of identifiable peptidergic neurons in Drosophila melanogaster.

The molecular basis of programmed cell death (PCD) of neurons during early metamorphic development of the central nervous system (CNS) in Drosophila melanogaster are largely unknown, in part owing to the lack of appropriate model systems. Here, we provide evidence showing that a group of neurons (vCrz) that express neuropeptide Corazonin (Crz) gene in the ventral nerve cord of the larval CNS undergo programmed death within 6 hours of the onset of metamorphosis. The death was prevented by targeted expression of caspase inhibitor p35, suggesting that these larval neurons are eliminated via a caspase-dependent pathway. Genetic and transgenic disruptions of ecdysone signal transduction involving ecdysone receptor-B (EcR-B) isoforms suppressed vCrz death, whereas transgenic re-introduction of either EcR-B1 or EcR-B2 isoform into the EcR-B-null mutant resumed normal death. Expression of reaper in vCrz neurons and suppression of vCrz-cell death in a reaper-null mutant suggest that reaper functions are required for the death, while no apparent role was found for hid or grim as a death promoter. Our data further suggest that diap1 does not play a role as a central regulator of the PCD of vCrz neurons. Significant delay of vCrz-cell death was observed in mutants that lack dronc or dark functions, indicating that formation of an apoptosome is necessary, but not sufficient, for timely execution of the death. These results suggest that activated ecdysone signaling determines precise developmental timing of the neuronal degeneration during early metamorphosis, and that subsequent reaper-mediated caspase activation occurs through a novel DIAP1-independent pathway.

Animals↗

PubMed1993

Ventricular mitochondrial gene expression during development and following embryonic ethanol exposure.

The effects of chronic embryonic ethanol exposure were evaluated in chick ventricular muscle. Ethanol treatments were administered on embryonic days 11, 13, 15, and 17 and chicks were sacrificed at various time points following treatments. Fluctuations in embryonic blood ethanol levels were examined following treatments. Developmental increases in the activities of mitochondrial enzymes, cytochrome oxidase (CO) and citrate synthase (CS), were observed. Ethanol exposure resulted in a depression in CO activity, but not CS activity. Since, a maximal depression in CO activity was seen with ethanol treatments of 75 mg/100 g, this dosing paradigm was adopted for subsequent experiments. A tissue-specific effect of ethanol was demonstrated as CO activity was unchanged in atrial, liver, pectoralis, and brain tissues. The role of mitochondrial DNA replication and transcription during the developmental up-regulation and ethanol-induced down-regulation of CO activity was evaluated using a cDNA probe for cytochrome oxidase subunit III (COIII). The relative levels of COIII mRNA and mitochondrial DNA (cpm/mg protein) decreased by 3-fold and 4-fold, respectively, across the developmental time course, while CO activity increased by 3.5-fold. Therefore, increases in mitochondrial DNA and mitochondrial mRNA transcripts are unlikely to be responsible for the developmentally-regulated increases in CO activity. Similarly, embryonic ethanol exposure failed to elicit alterations in COIII mRNA levels, indicating that the ethanol-induced depression in CO activity was not transcriptionally regulated. However, ventricular mitochondrial DNA concentrations were elevated in ethanol-treated embryos, indicating that ethanol-exposure either directly or indirectly induces mitochondrial DNA replication.

Animals↗

PubMed1984

Prenatal haloperidol alters striatal dopamine and opiate receptors.

Dopamine receptors were chronically blocked with haloperidol during prenatal development. The treatment resulted in a large decrease in [3H]naloxone binding to striatal opiate receptors and increased [3H]spiperone binding to dopamine receptors with these effects being apparent on the day of birth (P0). The autoradiographically visualized patterns of receptor distribution were unaltered. At 16 days, postnatally (P16), a period that marks the end of the postnatal spurt in brain growth, dopamine receptor binding was still elevated and opiate receptor binding was still diminished. The differential effect of haloperidol on the density and developmental time course of the dopamine and non-dopamine systems suggests that complex developmental interactions normally occur, and that these can be disrupted by maternal administration of neuroleptic drugs.

Animals↗

PubMed1988

Parental agreement on child rearing during early childhood and the psychological characteristics of adolescents.

In previous research, an index of parental agreement regarding child-rearing orientations was found to relate to the quality of children's psychological functioning from 3 to 7 years of age. For this study, the parental agreement index, derived when their children were 3 years old, was related to a variety of psychological measures and personality descriptions obtained when the children were adolescents. Reliable differences were found in the patterning of relations for boys and girls wherein parental agreement during early childhood was associated with tested intelligence, aspects of moral judgment, and dimensions of personality derived from self-reports for boys but not for girls. For adolescent girls, early parental agreement was associated with the congruence of "self" and "ideal-self" descriptions (i.e., self-esteem). For both girls and boys, parental agreement was associated with personality descriptions provided by observers; however, it was only in the sample of girls that early parental agreement significantly correlated with Q sort criterion scores referencing ego-undercontrol and ego-resiliency. These findings suggest that early family socialization experiences are importantly but differently salient for boys and girls with respect both to psychological content and the developmental timing of effects. The data suggest that socialization researchers consider the likelihood that developmental paths to competence differ markedly for girls and boys.

Adolescent↗

PubMed2000

Single SPECT measures of cerebral cortical perfusion reflect time-index estimation of dementia severity in Alzheimer's disease.

UNLABELLED: To determine the relationship between cerebral cortical blood flow loss and the temporal development of the dementia in Alzheimer's disease (AD), SPECT was studied in a cross section of AD patients with a broad range of impairment. METHODS: Thirty patients with a diagnosis of probable AD had their mini-mental state examination scores transformed into time-index values to give an estimation of dementia severity relative to the developmental time course. SPECT images were obtained using 99mTc-ethyl cysteinate dimer and a 3-head camera. Cortical surface perfusion was analyzed, including modified Talairach standardization, to obtain cortical elements from the convexity (each representing about 0.25 cm2 at the surface, 6.6-mm cortical depth) referenced to the mean perfusion of the full greater cerebellar hemisphere. These element ratios were analyzed (individually and by averages of estimated Brodmann's areas and brain regions) using linear regression with the time-index value. RESULTS: For individual posterotemporal and inferoparietal Brodmann's areas (21, 22 and 39, 40, respectively) the correlation coefficients between cortical perfusion ratios and dementia severity ranged between -0.67 and -0.78 (P < 0.001). Perfusion ratios from these regions declined 2.5%-4.2% for each estimated year of progression. Prefrontal area perfusion showed less association with severity. Perfusion in primary cortical regions had no significant association with dementia severity. CONCLUSION: Cerebral cortical perfusion loss is temporally related to development of dementia. The spatial pattern of high, significant correlations between cortical perfusion and dementia severity shows a regional distribution that corresponds closely to the distribution of AD pathology described in autopsy studies.

Aged↗

PubMed2000

Molecular heterochrony in the early development of Drosophila.

Heterochrony, the relative change of developmental timing, is one of the major modes of macroevolutionary change; it identifies temporally disassociated units of developmental evolution. Here, we report the results of a fine-scale temporal study for the expression of the developmental gene hairy and morphological development in three species of Drosophila, D. melanogaster, D. simulans, and D. pseudoobscura. The results suggest that between and among closely related species, temporal displacement of ontogenetic trajectory is detected even at the earliest stage of development. Overall, D. simulans shows the earliest expression, followed by D. melanogaster, and then by D. pseudoobscura. Setting D. melanogaster as the standard, we find the approximate time to full expression is accelerated by 13 min, 48 s in D. simulans and retarded by 24 min in D. pseudoobscura. Morphologically, again with D. melanogaster setting the standard, initiation of cellularization is faster in D. simulans by 15 min, 42 s; and initiation of morphogenesis is faster in D. simulans by 18 min, 7 s. These results seem to be consistent with the finding that the approximate time to full expression of hairy is accelerated by 13 min, 48 s in D. simulans. On the other hand, the same morphological events are delayed by 5 min, 32 s, and by 11 min, 32 s, respectively, in D. pseudoobscura. These delays are small, compared with the 24-min delay in full expression. The timing changes, in total, seem consistent with continuous phyletic evolution of temporal trajectories. Finally, we speculate that epigenetic interactions of hairy expression timing and cell-cycle timing may have led to morphological differences in the terminal system of the larvae.

Animals↗

PubMedDate not supplied

How a child builds its brain: some lessons from animal studies of neural plasticity.

Although the potential vulnerability of children's brain development is generally recognized, relatively little is known about the timing, resiliency, or mechanisms involved. While animal research should be applied only cautiously to human policy, some findings do have important clinical implications. This paper briefly reviews animal studies demonstrating the effects of experience on brain structure. Contemporary theories emphasize the self-organizing potential of brain structure, particularly regions that seem to have evolved for the purpose of storing information. We emphasize three major findings: (1) many regions of the brain are responsive to experience, but they differ in the types of information stored and in their developmental timing. (2) One type of plasticity is typically embedded in a developmental program, and it requires appropriate timing and quality of the information stored for the animal's development to be normal. (3) Another category of plasticity stores information that is idiosyncratic and unpredictable, but is often useful for species such as humans that learn throughout their life span. We therefore expect that some aspects of human brain development use the first type of plasticity and that abnormal experience or deprivation may cause lasting harm to brain and behavior. However, because the other type of plasticity lasts a lifetime, efforts such as psychotherapy or social interventions may help heal a wounded brain.

Animals↗

PubMed2000

Variation in anuran embryogenesis: differences in sequence and timing of early developmental events.

Comparative embryology of closely related species can shed light on the evolution of developmental processes. An important mechanism in the evolution of developmental processes, which can lead to significant changes in larval or adult form, is variation in the sequence and timing of developmental events. We compared the development of 12 species of anurans, including a wide taxonomic range as well as a number of congeneric species. The comparison consisted of monitoring a series of external morphological markers and histological markers. For each species we noted the timing of each of the markers, using a uniform parameter of normalized time. We compared the normalized time of each of these events among the species, as well as the sequence of the events. Our analysis revealed many differences in sequence and in timing of developmental events. We mapped these differences on a cladogram of the studied species, using sequence units as discrete characters. The differences do not seem to be connected to the phylogenetic relations between the species or to any obvious ecological factors. We suggest a hypothetical ancestral sequence of developmental events, and discuss the possible factors that could have caused the observed variations from the ancestral sequence.

Animals↗

PubMed1996

Auditory development reflected by middle latency response.

The auditory middle latency response (MLR) seems to have a relatively long developmental time course, extending through the first decade of life. Characteristics of each MLR component change developmentally not only with respect to waveform morphology but also with respect to response reliability, dependence on awareness state, and stimulus rate. Both human and animal studies indicate that these complex changes may be a result of multiple generating systems that show multiple time courses of development. This framework has practical ramifications in that clinical and research studies of MLR in young children must take into account the development sequence. Furthermore, it cannot be assumed a priori that research results obtained from adults will apply to young children. The complexity of the process raises intriguing questions regarding the functional development of auditory perception.

Animals↗

PubMed1992

Comparisons of the development of auditory brainstem response latencies between cats and humans.

Developmental changes in the peak latencies of auditory brainstem responses (ABR) recorded from humans and kittens were compared to test the hypothesis that developmental time courses among mammals are the same when appropriately normalized. Response latencies were computed as the difference from adult latency and conceptional ages were represented as percentages relative to the age that ABR wave latencies achieved a criterion value within 0.2 ms of asymptotic latency (i.e., adulthood). An underlying assumption of this exercise is that far-field response latency is an appropriate index of overall 'auditory development'. Results of this analysis suggest that developmental changes in latency of responses arising within the auditory periphery are similar between humans and cats, when appropriately normalized, and that more central changes show less correspondence. Consequently, absolute time course differences for specific developmental parameters must be considered and caution should be exercised when extrapolating results acquired from one species to the other.

Acoustic Stimulation↗

PubMed1988

Expression of Epi 1, an epidermis-specific marker in Xenopus laevis embryos, is specified prior to gastrulation.

The induction of morphologically observable neural structures occurs as the result of tissue interactions between chordamesoderm and overlying ectoderm beginning at gastrulation. Since the future dorsal, and hence neural, side of the embryo is determined around the time of fertilization, we questioned whether the presumptive neural epithelium might have received some developmental instructions prior to contact with the migrating chordamesoderm. Epi 1, a cell surface antigen present only on epidermal epithelium was used as a marker to determine when epithelial cells have been programmed to express (or not express) this epidermal-specific molecule. We find that ligated animal halves of precleavage embryos already contain all the information necessary for expression of Epi 1 at the appropriate developmental time (early neurula). By at least the eight-celled stage, the epithelial cells derived from ventral animal blastomeres are much better at expressing the Epi 1 antigen than their dorsal counterparts. We suggest that the mechanisms responsible for expression of the Epi 1 antigen are localized within the animal hemisphere prior to the onset of cleavage. By the third cleavage division, dorsal animal cells appear to have received information which inhibits the subsequent expression of this epidermal antigen.

Animals↗

PubMed1996

Developmental versus conventional care: a comparison of clinical outcomes for very low birth weight infants.

The purpose of this research was to describe the clinical profile of very low birth weight (VLBW) infants receiving conventional versus developmental care during their hospitalization and to determine the appropriateness of developmental-care interventions. A phase-lag study with 124 preterm infants indicated that although there were no significant differences in individual clinical outcomes, developmental care had a significant effect on the physiologic stability of the infant over time. Developmental interventions were used for all infants receiving the developmental-care intervention, with varying frequency.

Developmental Biology↗

PubMedDate not supplied

Role of the 5-HT1A receptor in development of the neonatal rat brain: preliminary behavioral studies.

Serotonin exerts an influence on the prenatal development of rat brain. However, later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders. Therefore, the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development. As the 5-HT1A receptor has been shown to be involved in much of the developmental functions of serotonin, an agonist for this receptor, 8-hydroxy-DPAT (8-OH-DPAT), was used. Neonatal rat pups at three ages (postnatal days, PNDs) 3-10, 10-17 or 17-24) were injected daily with 1 mg/kg 8-OH-DPAT and evaluated for behavioral consequences. The youngest group showed accelerated incisor eruption and eye-opening, a possible consequence of 5-HT1A receptor interactions with epidermal growth factor (EGF). Behaviorally, the animals were more anxious. Animals treated from PND 10-17, showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field. The oldest animals (PND 17-24) showed no behavioral alterations, suggesting that this time length is beyond the critical period for serotonin's influence in brain development.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2026

Four-dimensional molecular mapping from a spatial snapshot reveals the dynamics of hair follicle organogenesis.

Understanding organ formation requires capturing molecular information simultaneously in three-dimensional (3D) space and across developmental time. To this end, we developed 3D DNase-Enhanced Expression Profiling (3DEEP), a tissue-clearing approach that removes genomic DNA to extend spatial transcriptomic profiling hundreds of microns into intact tissues. We applied 3DEEP to neonatal mouse skin, capturing hundreds of developing hair follicles across their organogenesis trajectory. Ordering follicles by molecularly inferred developmental age transformed this single spatial snapshot into a four-dimensional (3D + time) molecular map of organogenesis. This map revealed developmental dynamics spanning stem cell compartment stratification, emergence of new cell subtypes within the follicle, and cascading structural transformations leading to hair canal formation. Comparative analysis of Foxn1-deficient nude mice, a hairlessness model, revealed organ-wide changes in developmental dynamics, including delayed molecular progression, reduced coordination, and increased developmental instability, preceding overt structural defects. This work demonstrates how deep-tissue spatial transcriptomics can uncover hidden dynamics of organ formation.

Animals↗