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PubMed1998

Drosophila nerve cord culture: a tool for studying neural development.

The culture of explanted neural tissues has been a useful tool for the study of cellular and molecular neurobiology in vertebrates. We have developed a technique for the culture of explanted ventral nerve cords from Drosophila embryos. We have examined the morphology and dynamic behaviour of the growth cones that extend from these nerve cords, and the effect of calcium deprivation on the bundling of axons that are regenerated from the explanted tissue. This technique offers a unique opportunity to combine in vitro techniques for neuronal cell culture with the powerful techniques of genetic analysis that are available with Drosophila.

Animals↗

PubMed1998

The neural development and organization of letter recognition: evidence from functional neuroimaging, computational modeling, and behavioral studies.

Although much of the brain's functional organization is genetically predetermined, it appears that some noninnate functions can come to depend on dedicated and segregated neural tissue. In this paper, we describe a series of experiments that have investigated the neural development and organization of one such noninnate function: letter recognition. Functional neuroimaging demonstrates that letter and digit recognition depend on different neural substrates in some literate adults. How could the processing of two stimulus categories that are distinguished solely by cultural conventions become segregated in the brain? One possibility is that correlation-based learning in the brain leads to a spatial organization in cortex that reflects the temporal and spatial clustering of letters with letters in the environment. Simulations confirm that environmental co-occurrence does indeed lead to spatial localization in a neural network that uses correlation-based learning. Furthermore, behavioral studies confirm one critical prediction of this co-occurrence hypothesis, namely, that subjects exposed to a visual environment in which letters and digits occur together rather than separately (postal workers who process letters and digits together in Canadian postal codes) do indeed show less behavioral evidence for segregated letter and digit processing.

Adult↗

PubMed2000

Neural development and neurodegeneration: two faces of neuropathy target esterase.

Neuropathy target esterase (NTE) is an integral membrane protein in vertebrate neurons. Recent evidence suggests that NTE plays an important role in neural development, possibly via involvement in a signalling pathway between neurons and glial cells. NTE is a member of a novel protein family, represented in organisms from bacteria to man. NTE comprises an N-terminal regulatory domain (with some sequence similarity to cyclic nucleotide-binding proteins) and a C-terminal catalytic domain: the latter has three predicted transmembrane segments and requires membrane-association for activity. In vitro, NTE potently catalyses hydrolysis of phenyl valerate: however, its physiological substrate is likely to be a metabolite of a much longer chain carboxylic acid, possibly associated with cell membranes. NTE was discovered originally as the primary target for those organophosphorus esters (OPs) which cause a delayed neuropathy with degeneration of long axons in peripheral nerves and spinal cord. Paradoxically, NTE's catalytic activity appears redundant in adult vertebrates. Neuropathic OPs react covalently with NTE in a rapid two-step process which not only inhibits catalytic activity but also leaves a negatively-charged OP group attached to the active site serine. The latter event is proposed to induce a toxic gain of function in NTE. OP-modified NTE somehow engenders a "chemical transection of the axon". In turn, this leads to calcium entry, elevation of axonal calpain activity and Wallerian-type degeneration. The net damage to peripheral nerve axons is a balance between ongoing degenerative and repair processes: the latter involve serine hydrolases which can be inhibited by the same OPs used to modify NTE.

Animals↗

PubMed2002

Applying genomics technologies to neural development.

Genomic technologies have evolved from a minority interest to a set of generally applicable, powerful tools. Recent studies have demonstrated that such tools are of great use in studies of neural development, particularly when allied to advances in data analysis and methods for analyzing gene function.

Animals↗

PubMed1997

A chimeric enhancer-of-split transcriptional activator drives neural development and achaete-scute expression.

Drosophila melanogaster neurogenesis requires the opposing activities of two sets of basic helix-loop-helix (bHLH) proteins: proneural proteins, which confer on cells the ability to become neural precursors, and the Enhancer-of-split [E(spl)] proteins, which restrict such potential as part of the lateral inhibition process. Here, we test if E(spl) proteins function as promoter-bound repressors by examining the effects on neurogenesis of an E(spl) derivative containing a heterologous transcriptional activation domain [E(spl) m7Act (m7Act)]. In contrast to the wild-type E(spl) proteins, m7Act efficiently induces neural development, indicating that it binds to and activates target genes normally repressed by E(spl). Mutations in the basic domain disrupt m7Act activity, suggesting that its effects are mediated through direct DNA binding. m7Act causes ectopic transcription of the proneural achaete and scute genes. Our results support a model in which E(spl) proteins normally regulate neurogenesis by direct repression of genes at the top of the neural determination pathway.

Animals↗

PubMed1987

The differing effects of occipital and trunk somites on neural development in the chick embryo.

In all higher vertebrate embryos the sensory ganglia of the trunk develop adjacent to the neural tube, in the cranial halves of the somite-derived sclerotomes. It has been known for many years that ganglia do not develop in the most cranial (occipital) sclerotomes, caudal to the first somite. Here we have investigated whether this is due to craniocaudal variation in the neural tube or crest, or to an unusual property of the sclerotomes at occipital levels. Using the monoclonal antibody HNK-1 as a marker for neural crest cells in the chick embryo, we find that the crest does enter the cranial halves of the occipital sclerotomes. Furthermore, staining with zinc iodide/osmium tetroxide shows that some of these crest-derived cells sprout axons within these sclerotomes. By stage 23, however, no dorsal root ganglia are present within the five occipital sclerotomes, as assessed both by haematoxylin/eosin and zinc iodide/osmium tetroxide staining. Moreover, despite this loss of sensory cells, motor axons grow out in these segments, many of them later fasciculating to form the hypoglossal nerve. The sclerotomes remain visible until stages 27/28, when they dissociate to form the base of the skull and the atlas and axis vertebrae. After grafting occipital neural tube from quail donor embryos in place of trunk neural tube in host chick embryos, quail-derived ganglia do develop in the trunk sclerotomes. This shows that the failure of occipital ganglion development is not the result of some fixed local property of the neural crest or neural tube at occipital levels. We therefore suggest that in the chick embryo the cranial halves of the five occipital sclerotomes lack factors essential for normal sensory ganglion development, and that these factors are correspondingly present in all the more caudal sclerotomes.

Animals↗

PubMed2005

The assembly of POSH-JNK regulates Xenopus anterior neural development.

POSH (Plenty of SH3s) has distinct roles as a scaffold for specific c-Jun N-terminal kinase (JNK) signaling modules and as an E3 ubiquitin ligase. The physiological function of POSH remains unclear, however, and its possible involvement in developmental processes motivated the present study wherein the Xenopus orthologue of POSH (xPOSH) was examined for its potential role during Xenopus early embryogenesis. Loss-of-function analysis using morpholino oligonucleotides demonstrated that POSH was essential for Xenopus anterior neural development, although not Spemann organizer formation and early neurogenesis, through the formation of an active JNK signaling complex. Moreover, POSH-mediated JNK pathway was essential for apoptosis in anterior neural tissues. Finally, the present findings demonstrate that RING (Really Interesting New Gene) domain-mediated E3 ubiquitin ligase activity of POSH was not involved in POSH-mediated JNK pathway in vivo. Together, these data suggest that the active JNK signaling complex formed of POSH and the JNK module is essential for the expression of anterior neural genes and apoptosis in Xenopus anterior development.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Neural development: The semantics of axon guidance.

Recent studies of the semaphorin family of axon guidance signals and their receptors have revealed a surprising versatility in the ways that they can be used solve problems in neural development, and provided new opportunities for understanding how guidance information is interpreted beneath the cell surface.

Animals↗

PubMed1997

A splice variant of Dp71 lacking the syntrophin binding site is expressed in early stages of human neural development.

Dp71, a 71 kDa C-terminal isoform of dystrophin, is the major product of the DMD gene in brain. Two alternatively spliced transcripts of Dp71 were amplified by RT-PCR from different areas of human fetal neural tissue. Both transcripts were spliced out of exons 71 and 78. The shorter transcript was also alternatively spliced of exons 72-74, a region comprising the coding sequence for the binding site to syntrophin, one component of the dystrophin-associated protein complex. Results indicate that alternatively spliced forms of Dp71 are regulated during human neural development.

Alternative Splicing↗

PubMed2001

Notch signalling and the initiation of neural development in the Drosophila eye.

Neural determination in the Drosophila eye occurs progressively. A diffusible signal, Dpp, causes undetermined cells first to adopt a 'pre-proneural' state in which they are primed to start differentiating. A second signal is required to trigger the activation of the transcription factor Atonal, which causes the cells to initiate overt photoreceptor neurone differentiation. Both Dpp and the second signal are dependent on Hedgehog (Hh) signalling. Previous work has shown that the Notch signalling pathway also has a proneural role in the eye (as well as a later, opposite function when it restricts the number of cells becoming photoreceptors - a process of lateral inhibition). It is not clear how the early proneural role of Notch integrates with the other signalling pathways involved. We provide evidence that Notch activation by its ligand Delta is the second Hh-dependent signal required for neural determination. Notch activity normally only triggers Atonal expression in cells that have adopted the pre-proneural state induced by Dpp. We also report that Notch drives the transition from pre-proneural to proneural by downregulating two repressors of Atonal: Hairy and Extramacrochaetae.

Animals↗

PubMed2005

Use of short hairpin RNA expression vectors to study mammalian neural development.

The use of RNA interference (RNAi) in mammalian cells has become a powerful tool for the analysis of gene function. Here we discuss the use of DNA vectors to produce short hairpin RNAs (shRNAs) and inhibit gene expression in mammalian neural progenitors and neurons. Protocols are presented for introducing shRNA vectors into mouse P19 cells differentiated as neurons in vitro and for electroporation of shRNA vectors into primary neural progenitors from the embryonic mouse dorsal telencephalon (prospective cerebral cortex). Transfected primary cortical progenitors can be differentiated in vitro either in dissociated culture or organotypic slice culture. The use of shRNA vectors for RNAi provides a versatile approach to understand gene function during mammalian neural development.

Animals↗

PubMed1980

Characterization of intercellular junctions in the caudal portion of the developing neural tube of the chick embryo.

The types of intercellular junctions present within caudal levels of the chick neural tube (i.e., future lower thoracic and lumbosacral regions of the spinal cord) were determined by freeze-fracture of stage 14 to 16 embryos. Two levels of the developing neural tube were examined: the region of the neurulation overlap zone--consisting of primary neural tube dorsally and secondary neural tube ventrally--and the portion of the primary neural tube located just cranial to the overlapping region. Gap junctions were the most numerous type of intercellular junction present within the primary neural tube. These junctions were located primarily in juxtaluminal areas, near the apices of neuroepithelial cells, and sometimes also at the bases of these same cells. In addition, focal, poorly defined tight junctions occasionally occupied juxtaluminal regions of the primary neural tube. The medullary cord (i.e., the immediate precursor of the secondary neural tube) and secondary neural tube contained gap junctions exclusively. Gap junctions were first found in these areas at the lateral borders of the medullary cord, concomitant with formation of this structure, and then at the interface between the elongated, peripheral cells of the cord and the irregularly shaped and loosely arranged central cells of this structure. Finally, gap junctions were distributed radially around secondary lumina formed by cavitation. The precise spatial and temporal correlation between the appearance of gap junctions and the specific changes occurring in cellular morphology and arrangement during secondary neurulation strongly suggest that gap junctions may have a role in coordinating cellular activities during formation of both the medullary cord and the secondary neural tube.

Animals↗

PubMed2003

Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences.

The receptor tyrosine kinases represent an important class of signal transduction molecules that have been shown to play critical roles in neural development. We report in the present study that the neuregulin receptor ErbB4 is preferentially expressed by interneurons that are migrating tangentially from the ventral to the dorsal rat telencephalon. ErbB4 immunoreactivity was detected in the medial ganglionic eminence as early as embryonic day (E) 13 at the inception of tangential migration. Prominent ErbB4-positive migratory streams consisting of cells double-labeled with ErbB4 and Dlx, a marker of tangentially migrating cells, were found to advance along the lower intermediate zone and the marginal zone from the ventrolateral to the dorsomedial cortex at E16-E18. After E20, the ErbB4-positive stream in the lower intermediate zone shifted towards the germinal zone and further extended via the cortex into the hippocampal primordium. ErbB4 was not expressed by Tbr1-positive glutamatergic projection neurons during development. ErbB4 was preferentially expressed by the majority of parvalbumin-positive interneurons and subsets of other GABAergic interneurons in the cerebral cortex and the hippocampus in adulthood. The early onset and preferential expression of ErbB4 in tangentially migrating interneurons suggests that neuregulin/ErbB4 signaling may regulate the development and function of telencephalic interneurons.

Animals↗

PubMed1999

Neural development in metatherian and eutherian mammals: variation and constraint.

A model for predicting the timing of neurogenesis in mammals (Finlay and Darlington [1995] Science 268:1578-1584) is here extended to an additional five metatherian species and to a variety of other events in neural development. The timing of both the outgrowth of axonal processes and the establishment and segregation of connections proves to be as highly predictable as neurogenesis. Expressed on a logarithmic scale, late developmental events are as predictable as early ones. The fundamental order of events is the same in eutherian and metatherian animals, but there is a curvilinear relation between the event scales of the two; for metatherians, later events are slowed relative to earlier events. Furthermore, in metatherians, the timing of developmental events is more variable than in eutherians. The slowing of late developmental events in metatherians is associated with their considerably longer time to weaning compared with eutherians.

Animals↗

PubMed2005

Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development.

Neural tube defects (NTDs) are prevalent human birth defects. Mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK), are implicated in facilitating neural tube closure, yet upstream regulators remain to be identified. Here, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepithelium. Mice deficient in MEKK4 develop highly penetrant NTDs that cannot be rescued by supplementation with folic acid or inositol. Unlike most mouse models of NTDs, MEKK4 mutant embryos display genetically co-segregated exencephaly and spina bifida, recapitulating the phenotypes observed in human patients. To identify downstream targets of MEKK4 during neural tube development, we examined the activity of MAP kinase kinase 4 (MKK4), a signaling intermediate between MAP kinase kinase kinase and JNK/p38. We found a significant reduction in MKK4 activity in MEKK4-deficient neuroepithelium at sites of neural tube closure. MAPK pathways are key regulators of cell apoptosis and proliferation. Analyses of the neuroepithelium in MEKK4-deficient embryos showed massively elevated apoptosis before and during neural tube closure, suggesting an antiapoptotic role for MEKK4 during development. In contrast, proliferation of MEKK4-deficient neuroepithelial cells appeared to be largely unaffected. MEKK4 therefore plays a critical role in regulating MKK4 activity and apoptotic cell death during neural tube development. Disruption of this signaling pathway may be clinically relevant to folate-resistant human NTDs.

Animals↗

PubMed2001

Embryonic XMab21l2 expression is required for gastrulation and subsequent neural development.

Cell fate determining gene mab-21 regulates the proper establishment of neural cell fate and sensory organ identity in nematode. Mammalian homologs of mab-21 have also been implicated to play critical roles in mid-, hindbrain and craniofacial differentiation. We report here the isolation of a mab-21 homolog, XMab21l2, from Xenopus. We showed that its expression in Xenopus was initiated at gastrulation and prominent signal was detected in neurulating embryos at the neural tube, the optic tissue, the developing midbrain, and the pharyngeal pouches. We demonstrated by RNA interference (RNAi), together with other antisense approaches, that XMab21l2 expression is required for the completion of gastrulation and subsequent neural development.

Amino Acid Sequence↗

PubMed2005

Learning-induced synchronization and plasticity of a developing neural network.

Learning-induced synchronization of a neural network at various developing stages is studied by computer simulations using a pulse-coupled neural network model in which the neuronal activity is simulated by a one-dimensional map. Two types of Hebbian plasticity rules are investigated and their differences are compared. For both models, our simulations show a logarithmic increase in the synchronous firing frequency of the network with the culturing time of the neural network. This result is consistent with recent experimental observations. To investigate how to control the synchronization behavior of a neural network after learning, we compare the occurrence of synchronization for four networks with different designed patterns under the influence of an external signal. The effect of such a signal on the network activity highly depends on the number of connections between neurons. We discuss the synaptic plasticity and enhancement effects for a random network after learning at various developing stages.

Algorithms↗

PubMed1991

Expression of gap junction genes during postnatal neural development.

The timing of appearance of mRNAs encoding gap junction proteins was examined during development of the rat and mouse brain. Complementary DNAs (cDNAs) specific for the mRNA for the liver-type gap junction protein, connexin32, and the heart-type gap junction protein, connexin43, were used to probe Northern blots of total RNA isolated from the forebrain and hindbrain of mice and rats at various times before and after birth. Prior to postnatal day 10, connexin32 mRNA is detectable only at low levels. By postnatal days 10 to 16, a sharp increase occurs in the level of this mRNA. This increase is detectable first in the hindbrain, and subsequently in the forebrain. In contrast, connexin43 mRNA is readily detectable at birth, and the level of this mRNA also increases during subsequent development. The developmental appearance of the gap junction proteins, connexin32 and connexin43, was similar to that of their respective mRNAs. These results indicate that the genes encoding connexin32 and connexin43 are differentially expressed during neural development.

Animals↗