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PubMed2025

Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.

Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.

Hematopoietic Stem Cells↗

PubMed2025

Nuclear-lamin-guided plastic positioning and folding of the human genome.

The human genome exhibits a highly ordered hierarchical architecture, yet the mechanisms governing its large-scale organization remain poorly understood. Here, we generate lamin single-, double-, and triple-knockout human embryonic and mesenchymal stem cells (hESCs and hMSCs) to investigate the role of lamins in the spatial organization of the human genome. Complete lamin depletion in hMSCs triggers extensive genome repositioning, disrupts chromosome territories, and dissolves long-range compartment clustering and mega-loops. Lamin loss affects both the nuclear periphery and interior, causing partial inversion and dispersion of nuclear speckles, accompanied by reduced global transcription and impaired stem cell homeostasis. Re-expression of wild-type lamin A, which interacts with the speckle scaffold protein SON, partially restores the organizational and transcriptional defects, while the disease-associated E161K mutant disrupts SON binding and shows limited recovery. Our results elucidate the multifaceted roles of lamins in nuclear organization and link their dysfunction to the pathogenesis of laminopathies.

Humans↗

PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗

PubMed2025

In vivo differentiation of embryonic cells devoid of key reprogramming factors.

Embryonic cell differentiation depends on reprogramming of the oocyte and sperm nucleus into a transient totipotent state. In zebrafish, this coincides with genome activation, which is regulated by the pioneer factors Nanog, Pou5f3, and Sox19b (NPS). Here, we investigate the role of NPS in developmental reprogramming and differentiation by analyzing the fate of NPS mutant cells in a wild-type embryo using single-cell RNA-seq. We find that many cells fail to activate transcription or undergo cell death, while others acquire gene expression profiles that resemble germ cells, neural progenitors, and motoneuron states. These cells achieve intermediate transcriptional states, revealing the essential role of NPS in coordinating nuclear and cytoplasmic reprogramming and preventing the premature activation of lineage-specific differentiation programs. These results demonstrate that most developmental programs require developmental reprogramming by NPS, yet some cells can bypass transient totipotency to achieve intermediate developmental states resembling wild-type states in vivo.

Animals↗

PubMed2025

Multi-omics analyses reveal DjTcf4 critical for proper timing of differentiation in planarian regeneration.

The blastema is key to forming complete tissues in regenerating Dugesia japonica (D. japonica). However, the dynamic changes in cellular compositions and transcription landscapes in blastema during regeneration are understudied. Here, through genome reannotation, 3D spatial transcriptome construction, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses of changes in gene expression and chromatin structures, we delineate key transcription factors regulating the developmental trajectories of major cell clusters in the regenerating head. Importantly, we find that the T cell factor 4 (DjTcf4)-positive cells highly accumulate at wound areas, and its gene network is critical for the proper timing of development during regeneration in multiple progenitor cells. Depletion of DjTcf4 and its target genes leads to singular eye and/or dull tail phenotypes and delays regeneration. Taken together, we build multi-omics atlases in D. japonica and reveal the noncanonical function of the DjTcf4 network in developmental pattern formation, laying a foundation for studies of regeneration in D. japonica.

Animals↗

PubMed1992

Ontogenesis of the pyramidal cell of the mammalian neocortex and developmental cytoarchitectonics: a unifying theory.

The prenatal development of the mammalian neocortex has been analyzed, with the rapid Golgi method, in a variety of experimental animals (hamster, mouse, rat, and cat) and in humans. A new developmental conception of the structural organization of the mammalian neocortex is discussed. Neocortical development begins with the establishment of the primordial plexiform layer (PPL) which precedes and is a prerequisite for the subsequent formation of the cortical plate (CP). The formation of the CP occurs, in its entirety, within the PPL. During its development, three fundamental neuronal events occur: migration, early differentiation, and late maturation. All migrating neurons, travelling on radial glial fibers, reach layer I, develop an apical dendrite, and establish contacts with its elements. These newly differentiated neurons assume similar morphology resembling embryonic pyramidal cells. As such, an early differentiation stage common to all neurons of the CP is established. During the late maturation stage, all CP neurons acquire their specific phenotypic structural and functional features. Only pyramidal neurons retain and expand their original connections with layer I while other neuronal types lose these connections. The pyramidal cell is redefined in developmental terms: the neocortex's pyramidal cell is both structurally and functionally locked into position between layer I and the cortical depth of its soma. During mammalian evolution pyramidal cells are forced to structurally and functionally elongate their apical dendrite outwardly to accommodate an increasing amount of information without losing either their original anchorage to layer I or their cortical depth. This unique property of pyramidal neurons is considered to be a mammalian innovation. Based on these observations, a unifying developmental cytoarchitectonic theory applicable to all mammals is proposed. The theory considers the CP to be a mammalian innovation and to represent a single, stratified, and expanding telencephalic nucleus. The theory envisions the mammalian neocortex as an open biological system capable of progressive expansion by the recruitment and transformation of primitive neurons from upper layer II into pyramidal cells. Hence, the number of pyramidal cell strata increases over the course of mammalian phylogeny. The developmental roles of layer I in the migration of neurons, formation of the CP, unique morphology of pyramidal cells, and overall structural organization of the mammalian neocortex are emphasized.

Animals↗

PubMed1990

The in vitro activation of cyclophosphamide in the Hydra Developmental Toxicology Assay.

The proteratogen cyclophosphamide (CP) was tested in the Hydra Assay in the presence and absence of an in vitro metabolic activation package (MAP) consisting of rat hepatic microsomes (0.06 nmol P450/ml), 500 microM NADPH, and 25 microM MgCl. This metabolic system was developed through a series of interrelated biochemical and biological assays to provide maximum cytochrome P450 mixed-function monooxygenase (MFO) metabolic capacity while controlling the inherent toxicity of the hepatic preparation and the attendant cofactors. Bioactivation of CP was confirmed under standard hydra assay conditions of pH 7.0 and 20 degrees C and compared with activation at 37 degrees C. Estimation of total metabolic capacity and verification of activation were made through the appearance of alkylating metabolites both in the absence and in the presence of hydra. Chemical exposure was maintained throughout the 92 +/- 2 hr assay with periodic renewal of media (and additives) at 4, 20, 28, 42, and 66 hr of incubation. Inclusion of bioactivation increased the toxicity of CP by two orders of magnitude. The minimal affective concentration in the adult and developmental portions of the assay was decreased from 4000 to 20 micrograms CP/ml and from 1000 to 4 micrograms CP/ml, respectively. By limiting the inherent toxicity of the MFO package, it was possible to avoid pulse-type exposures and ensure that all ontogenic stages were exposed to active metabolites. The addition of metabolic activation capacity to an in vitro assay, while not essential, markedly enhances its utility and breadth of application in developmental toxicity safety evaluations.

Animals↗

PubMedDate not supplied

[Perinatal events and handicaps].

It is difficult to assess how large is the proportion of handicap in the pediatric age related to perinatal events; this is mainly due to the following reasons: lack of uniform criteria and accuracy in defining both "handicap" and the "perinatal period"; variable involvement of perinatal factors in the genesis of the different types of impairment; and multifactorial origin of most sensory, neural and developmental damages. For the same reasons it is no easy to assess if handicaps of perinatal origin are declining or increasing with time. Cerebral palsy (CP), retinopathy of prematurity (ROP), deafness and relational problems are probably the clinical conditions most strictly related to perinatal events, tough recently biological and familial prenatal factors have also been proposed as important antecedents of CP. No important variation in the incidence of CP has been reported for the last 20 years, notwithstanding a supposed better perinatal care as documented by the decreased neonatal mortality; on the contrary a new epidemic of ROP is being described. This is probably the consequence of the increasing survival of babies at highest risk for subsequent handicap, namely those weighing less than 1500 gm and, chiefly, those weighing less than 1000 gm. Available data on the incidence or prevalence of deafness in infancy do not permit a meaningful analysis of their variations with time. Perinatal asphyxia, neonatal convulsions, intraventricular hemorrhage, CNS leukomalacia, mechanical ventilation and mother-infant separation are probably the most important "markers" of risk for subsequent sequelae; they must be distinguished from the "causes", which are unknown in many instances. Owing to this difficulty it is not possible to establish a straight correlation between perinatal care and handicap. The strategy of intervention must be aimed at the prevention of the situations outlined above, and it must rely both on technical and political solutions, which include the prevention of preterm birth, an effective regionalization of care and a constant evaluation of the results.

Asphyxia Neonatorum↗

PubMedDate not supplied

Developmental pharmacology and toxicology: biotransformation of drugs and other xenobiotics during postnatal development.

The following conclusions can be drawn: Depending on reaction type, species (strain), organ (tissue) and sex (in rats and mice) both phase I and phase II ractions show developmental patterns with maximum activities in juvenile or young adult animals. In man drug disposition in newborns is also generally much lower than in children and young adults. Mammals with long gestation periods are born with considerable activities and adult values are reached earlier than in animals with short gestation periods. Highest activities (with very few exceptions) are observed in liver postnatally. With increasing age, in all laboratory animals and in man, a decline of biotransformation capacity is observed. Most of these reactions are inducible by inducers of the phenobarbital-, 3-methylcholanthrene- and tetrachlorodibenzo-p-dioxine-, steroid- or alcohol-type. Inducibility also depends on reaction type, species (strain), organ (tissue) and sex (in rats and mice). Inducibility begins in the earliest embryonic stage and reaches high rates in species with long gestation periods before birth, and at or after birth in species with short gestation periods. The beginning of high inducibility depends also on inducer types and the induced parameter. Inducible reactions can be increased in immature as well as in very old animals up to or above the level of adult animals. Isozymes may show different developmental patterns and inducibilities. Development and induction of isozymes catalyzing different reactions can be triggered in clusters. There is increasing evidence that basic biotransformation activities as well as their inducibilities by foreign compounds are essentially influenced by a kind of temporal genetic control during the whole life span. When we compared different monooxygenase reactions and their inducibility (Klinger et al., 1968) both the presence of P450 isozymes and their different inducibility as well as their different developmental pattern became evident, the direct proof of which was given 10 years later by the Nebert group (Atlas et al. 1977). Functional heterogeneity was demonstrated by differential development and inducibility by glucocorticoids also for UDP-glucuronosyl transferase (Wishart, 1978): in the rat the increased fetal glucocorticoid activity between days 17 and 20 of gestation triggers the surge to adult or higher than adult activities. This cluster of the so-called late fetal glucuronyltransferase group is distinctly different from the neonatal or postnatal cluster with peak values after birth and a pronounced inducibility by 3-methylcholanthrene, but not by steroids. These different transferase clusters can be differentiated by different substrates, too. To get an overview on the postnatal development of the most important phase I and phase II reactions and also for the heme biosynthetic pathway as a prerequisite for the P450 synthesis, a compilation of literature data similar to a score was constructed with the aim to recognize parallel developments, possible common control and regulation mechanisms, cp. Klinger et al. 1987, cp. also Figs. 1-3. Evidently different developmental patterns can be observed, direct connections or dependencies cannot be detected. Thus different concentrations resp. activities of different P450 forms during ontogenetic development are influenced by many factors on the transscriptional and posttransscriptional level. Reviews on concepts and therories of development and aging have been published by several authors respectively editors (cp. Klinger, 1996). But there is no convincing concept or proof on the molecular-biological basis of an internal clock which regulates and controls individual development, aging and death.

Age Factors↗

PubMedDate not supplied

Effect of intraocular lens design on migration of lens epithelial cells onto the posterior capsule.

PURPOSE: To find the conditions that prevent posterior capsule opacification through in vitro analysis of the relationship between intraocular lens (IOL) optic configuration and lens epithelial cell (LEC) migration. SETTING: Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, Okazaki, Japan. METHODS: In a preliminary experiment, we measured the size of the capsular bag of rabbits at 8, 16, 20, and 26 weeks of age. The size of a 20-week-old capsular bag was the same size as the capsular bag in senescent Japanese eyes. We isolated the capsular bags in 20- and 8-week-old rabbits. The bags along with a biconvex (BC), convex-plano (CP), or no IOL (C) were cultured, and the eyes were divided into one of six groups (8W-C, 8W-BC, 8W-CP, 20W-C, 20W-BC and 20W-CP), each including six specimens. RESULTS: Two specimens in the 8W-CP group completely blocked LEC migration at the optic edge. All specimens in the 20W-CP group and one in the 20W-BC group showed cell aggregation along the optic edge. None of the other specimens in the BC and C groups blocked migration or showed cell aggregation. CONCLUSIONS: In the rabbit-model study, the convex-plano lens was superior to the biconvex lens in inhibiting migration of LECs. A firm contact between the IOL and the posterior capsule blocked the migration.

Animals↗

PubMed2000

Differential uptake and catabolism of prostaglandin (PG)E(2) versus PGF(2alpha) in the sheep choroid plexus during development.

The early postnatal decrease in prostaglandin (PG)E(2) levels in cerebrospinal fluid (CSF) likely contributes to the establishment of continuous breathing. To elucidate mechanisms underlying this event, choroid plexuses from lateral (L-CP) and third/fourth (III/IV-CP) ventricles were incubated with [3H]-PGE(2) and label uptake (tissue-to-medium ratio for radioactivity, T/M) and catabolism (%radioactivity associated with metabolites, PGM) were measured. [3H]-PGF(2alpha) was a reference. Uptake of [3H]-PGE(2) was lower than [3H]-PGF(2alpha) in the term fetus (L-CP: 5.9+/-0.5 vs. 9.6+/-0. 9, n=11; III/IV-CP: 2.7+/-0.4 vs. 7.7+/-1.0, n=5) and 17 d lamb (L-CP: 5.3+/-0.8 vs. 11.0+/-1.2, n=7; III/IV-CP: 3.1+/-0.2 vs. 11. 6+/-2.8, n=3 and 4, respectively). This difference was not significant in the pregnant adult. Release of the two compounds was similar and did not change with age. [3H]-PGE(2) uptake was reduced by probenecid (1 mM) and excess PG (60 microM PGE(2) or PGF(2alpha)). Excess PG also reduced catabolism in the fetus, which was extensive for [3H]-PGE(2) and [3H]-PGF(2alpha)60%). In the lamb, catabolism remained high for [3H]-PGE(2) (L-CP: 64+/-4%, n=7; III/IV-CP: 41+/-4%, n=3), but not [3H]-PGF(2alpha) (L-CP: 26+/-4%, n=7; III/IV-CP: 4+/-1%, n=4). In the pregnant adult, catabolism was above background only for [3H]-PGE(2) in the L-CP (26+/-5%, n=11). Unlike the perinatal animal, this catabolism was reduced by probenecid. In conclusion, PGE(2) uptake and catabolism operate independently in the choroid plexus from perinatal sheep. Differences between PGE(2) and PGF(2alpha) are developmentally-regulated for both mechanisms. While neither process explains the postnatal decrease in CSF PGE(2), both may help keep CSF levels low during early postnatal development.

Adult↗

PubMed2004

Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells.

Mature neocortical layers all derive from the cortical plate (CP), a transient zone in the dorsal telencephalon into which young neurons are continuously delivered. To understand cytogenetic and histogenetic events that trigger the emergence of the CP, we have used a slice culture technique. Most divisions at the ventricular surface generated paired cycling daughters (P/P divisions) and the majority of the P/P divisions were asymmetric in daughter cell behavior; they frequently sent one daughter cell to a non-surface (NS) position, the subventricular zone (SVZ), within a single cell-cycle length while keeping the other mitotic daughter for division at the surface. The NS-dividing cells were mostly Hu+ and their daughters were also Hu+, suggesting their commitment to the neuronal lineage and supply of early neurons at a position much closer to their destiny than from the ventricular surface. The release of a cycling daughter cell to SVZ was achieved by collapse of the ventricular process of the cell, followed by its NS division. Neurogenin2 (Ngn2) was immunohistochemically detected in a certain cycling population during G1 phase and was further restricted during G2-M phases to the SVZ-directed population. Its retroviral introduction converted surface divisions to NS divisions. The asymmetric P/P division may therefore contribute to efficient neuron/progenitor segregation required for CP initiation through cell cycle-dependent and lineage-restricted expression of Ngn2.

Animals↗

PubMed2005

Developmental and regional expression of heparan sulfate sulfotransferase genes in the mouse brain.

Heparan sulfate (HS) binds with various proteins including growth factors, morphogens, and extracellular matrix molecules to regulate their biological functions. These regulatory interactions are considered to be dependent on the structure of HS, which is determined by HS sulfotransferases. To gain insights into the functions of HS sulfotransferases in the development of the nervous system, we examined the expression of these enzymes (3-O-sulfotransferase-1 [3-OST-1], -2, -4; 6-OST-1, -2, -3; and N-deacetylase /N-sulfotransferase-1 [NDST-1], -2, -3) by in situ hybridization and real-time reverse transcription-polymerase chain reaction (RT-PCR). The expression of these genes was spatiotemporally regulated. In the E16 cerebrum, the expression of these genes showed two patterns: (1) selective expression at cortical plate (CP) and ventricular zone (VZ) and (2) wider expression by the cells in the marginal zone (MZ), CP, subplate (SP), and VZ. At P1, most genes showed similar expression patterns, but after P7, these genes were expressed differentially in a layer-specific manner. In the P1 cerebellum, the external granule cell layer (EGL) expressed most genes, the expressions of which were down-regulated at P7. In contrast, Purkinje cells began to express many of these genes after P7. These complex expression patterns suggest that the structure of HS is altered spatiotemporally for regulating various biological activities in the developing brain including the proliferation of neuronal progenitors, extension of axons, and formation of dendrites. We discuss possible functional roles of these sulfotransferases in the signaling of several HS-binding proteins such as fibroblast growth factors, slit, netrin, and sonic hedgehog.

Animals↗

PubMed1996

Activation of brain-type cannabinoid receptors interferes with preimplantation mouse embryo development.

The recent identification and cloning of guanine nucleotide regulatory protein-coupled brain-type and spleen-type cannabinoid receptors (CB1-R and CB2-R, respectively) provide evidence that many of the effects of cannabinoids are mediated via these receptors. Our recent observation of expression of both CB1-R and CB2-R genes in the preimplantation mouse embryo suggests that it could also be a target for cannabinoids. Indeed, cannabinoid agonists interfered with preimplantation embryo development in vitro. To examine whether cannabinoid effects on preimplantation embryos are mediated via CB1-R, we developed rabbit antipeptide antibodies against the N-terminal region of CB1-R and examined the receptor protein in the blastocyst by Western blotting and its spatiotemporal distribution in preimplantation mouse embryos by immunohistochemistry. Cannabinoid binding sites in the blastocyst were examined by Scatchard analysis, while the reversibility of cannabinoid-induced embryonic arrest in vitro was monitored using a specific antagonist to CB1-R, SR141716A. Western blot analysis detected a major band of approximately 59 kDa and a minor band of approximately 54 kDa in the blastocyst. Immunocytochemistry detected this receptor protein from the 2-cell through the blastocyst stages. Scatchard analysis using 3H-anandamide (an endogenous ligand) showed a single class of binding sites in Day 4 blastocysts with an apparent Kd of 1.0 nM and Bmax of 0.09 fmol/blastocyst. Considering the total number of cells (approximately 50) and total protein content (approximately 20 ng) of a blastocyst, it is apparent that the mouse blastocyst has many more high-affinity receptors than those in the mouse brain (Kd: 1.8 nM and Bmax: 18.8 pmol/mg membrane protein). Cannabinoid agonists and the CB1-R antagonist SR141716A effectively competed for anandamide binding in the blastocyst. To determine whether cannabinoid inhibition of embryonic development could be reversed by SR141716A, 2-cell embryos were cultured in the presence of cannabinoid agonists with or without SR141716A for 72 h. Most of the 2-cell embryos cultured in the absence of the agonists developed into blastocysts (approximately 90%). In contrast, the addition of cannabinoid agonists anandamide, Win 55212-2, or CP 55,940 in the culture medium severely compromised embryonic development: more than 60% of the 2-cell embryos failed to develop to blastocysts. A reduction in trophectoderm cell numbers was noted in those blastocysts that escaped the developmental arrest in the presence of cannabinoid agonists. However, this reduction was corrected when embryos were cultured simultaneously with an agonist and SR141716A. Furthermore, embryonic arrest was reversed when embryos were cultured simultaneously in the presence of an agonist and SR141716A. The addition of SR141716A alone in the culture medium apparently had no effects on embryonic development: more than 90% of the embryos developed into blastocysts. The results suggest that the CB1 receptors in preimplantation mouse embryos are biologically active and cannabinoid effects on them are primarily mediated by these receptors.

Analgesics↗

PubMed2002

Cell-to-cell movement of the PVX 12K, 8K, or coat proteins may depend on the host, leaf developmental stage, and the PVX 25K protein.

The requirements for intercellular movement of Potato virus X (PVX) 12K, 8K, and coat proteins (CP) differed in two Nicotiana spp. Plasmids containing the green fluorescent protein (GFP) gene fused to PVX 12K, 8K, or CP genes were bombarded to tobacco leaves. Protein movement was observed in N. benthamiana but not N. tabacum leaves. GFP:12K and GFP:8K moved cell-to-cell in 25K-expressing transgenic N. tabacum source but not sink leaves. In N. tabacum, GFP:12K and GFP:8K intercellular movement depends on the 25K and leaf developmental stage. Leaves were bombarded using two biolistic delivery methods and the results were similar indicating that movement of GFP:12K or GFP:8K is independent of the delivery system. Mutations in 12K, 8K, and CP genes within the PVX genome inhibited viral intercellular movement in both Nicotiana spp. Thus plasmodesmata gating is not an essential function of these proteins for virus cell-to-cell movement. These proteins likely provide additional activities for virus cell-to-cell movement.

Biolistics↗

PubMed2001

Developmental analysis of ceruloplasmin gene and liver formation in zebrafish.

Formation of the liver in zebrafish has been analyzed during normal embryogenesis using ceruloplasmin (Cp) as a specific marker. The asymmetric expression of Cp has been detected in dorsal endoderm at 16 hpf and later in the early hepatic cells in the yolk sac. The liver primordium can be detected after 32 hpf. In oep-/- mutant, which lacks dorsal endoderm, the liver fails to form. In the notochordless flh-/- mutant, the asymmetry of the liver has been lost. Therefore the notochord, dorsal endoderm and endoderm of the yolk sac play a role in liver formation in zebrafish.

Amino Acid Sequence↗

PubMed2004

Movement and motor development in ELBW infants at 1 year is related to cognitive and motor abilities at 4 years.

A relationship between motor ability and cognitive performance has been previously reported. This study aimed to investigate the association between movement and cognitive performance at 1 and 4 years corrected age of children born less than 1000 g, and whether developmental testing of movement at 1 year is predictive of cognitive performance at 4 years. Motor development was assessed at both ages using the neurosensory motor developmental assessment (NSMDA) and motor development was classified as normal, or minimal, mild, moderate-severe dysfunction. Cognitive performance was assessed on the Griffith Mental Developmental Scale at 1 year and McCarthy Scales of Children's Abilities at 4 years. Subjects included 198 children of birthweight less than 1000 g. Of these 132 children returned for follow-up at the corrected ages of both 1 and 4 years. The 66 children not included had a slight increase in gestational age, while the mothers were younger and had a lower level of education. A significant association was found between NSMDA group classification at 1 year and cognitive performance at both 1 and 4 years (p<0.001; p<0.0001) and between the subscales of each test (1 year, p<0.0001; 4 years, p<0.001). Group classification of motor development at 1 year was predictive of cognitive performance at 4 years (p<0.0001) and this was independent of biological and social factors and presence of cerebral palsy (CP). The findings support a close link between motor and cognitive development in children born <1000 g and emphasise the advantage of detailed assessment of movement at 1 year.

Child Development↗

PubMed2006

Age-dependent participation of Ras-GRF proteins in coupling calcium-permeable AMPA glutamate receptors to Ras/Erk signaling in cortical neurons.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors (AMPARs) are ligand-gated sodium channels. Through their ability to mediate the majority of rapid excitatory transmission in the central nervous system, these neurotransmitter receptors have been shown to influence synaptic plasticity. Some of these receptors are also calcium-permeable (CP), and they also have been implicated in regulating synaptic plasticity, particularly in interneurons where their concentration is highest. However, the biochemical pathways emanating from CP-AMPARs that mediate these effects have not been well characterized. In this paper, we show that CP-AMPARs are the predominant AMPAR class responsible for activating the Ras/Erk kinase signaling cascade and the cAMP-response element-binding protein (CREB) transcription factor in the cortex of mature mice. Activation of Ras and Erk, but not CREB, occurs through the calcium/calmodulin regulated Ras-GRF1 and Ras-GRF2 exchange factors, which form AMPA-induced complexes with CP-AMPARs but not calcium-impermeable (CI) AMPARs in vivo. Furthermore, we show that CP-AMPARs are also the major AMPAR type to activate Ras/Erk signaling in pubescent mice; however, at this developmental stage Ras-GRF (guanine nucleotide-releasing factor) proteins are not involved. Finally, in neonatal animals CI-AMPARs, but not CP-AMPARs, are the predominant AMPAR type that activates Ras-Erk signaling and CREB in cortical neurons. This occurs indirectly through activation of L-type voltage-dependent calcium channels, an event that is also Ras-GRF-independent. Thus, Ras/Erk signaling and CREB activity induced by AMPARs occur through age-dependent mechanisms that likely make unique developmentally dependent contributions to synaptic function.

Animals↗