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PubMed1978

The ectomesenchymal-endodermal interaction system of Triturus alpestris in tissue culture: morphological and histochemical characterization of developing neural derivatives.

In the ectomesenchymal-endodermal interaction system (EEIS), a hanging drop culture in which an explant of neural fold from behind the prospective ear region of a Triturus alpestris neurula together with a piece of ventrolateral pharynx endoderm is cultivated, the differentiation of a variety of neural crest-derived cells (nerve cells, pigment cells, cartilage cells, perichondrial cells, Schwann cells) can be followed. While cartilage cells develop only in contact to pharynx endoderm, the differentiation of neural crest-derived neuroblasts, rhombencephalic brain derivatives and epidermis which segregate from the explant of neural fold, does not depend on the presence of pharynx endoderm. The development of neural derivatives was studied with respect to morphology and histochemistry. Outgrowing axons may be observed 2-3 days after the beginning of cultivation. The fibres increase in thickness and length during further development and frequently make contact with other cells. Cytophotometric measurements of Feulgen-stained neural crest cells in the EEIS revealed that 72% of cells had a 2c and 9% a 4c DNA content while 18% were in S phase. Nerve cells had a 2c DNA content and prospective chondroblasts were in S phase. About 60-70% of S phase and 4c cells were observed at the margin of the culture. Neural crest-derived neuroblasts and melanoblasts obviously reacted catecholamine-positive upon formaldehyde-induced fluorescence (FIF), while axons from the brain derivative were catecholamine-negative but acetylcholinesterase (AChE)-positive. Neural crest cells prior to visible differentiation and neural crest-derived neuroblasts were AChE-negative. Catecholamine-positive (= fluorescing) cells can be recognized as either neuro- or melanoblasts prior to displaying phenotypic features. In cultures incubated with 3H-Dopa, freeze-dried, treated with the FIF-procedure, and subjected to autoradiography, only melanoblasts specifically accumulated the label.

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PubMed2006

Transgenic mice expressing PAX3-FKHR have multiple defects in muscle development, including ectopic skeletal myogenesis in the developing neural tube.

The t(2;13) chromosomal translocation is found in the majority of human alveolar rhabdomyosarcomas (RMS). The resulting PAX3-FKHR fusion protein contains PAX3 DNA-binding domains fused to the potent transactivation domain of FKHR, suggesting that PAX3-FKHR functions to deregulate PAX3-specific target genes and signaling pathways. We previously developed transgenic mice expressing PAX3-FKHR under the control of mouse Pax3 regulatory sequences to test this hypothesis. We reported that PAX3-FKHR interferes with normal Pax3 developmental functions, with mice exhibiting neural tube and neural crest abnormalities that mimic those found in Pax3-deficient Splotch mice. Here we expanded those studies to show that developmental expression of PAX3-FKHR results in aberrant myogenesis in the developing somites and neural tube, leading to ectopic skeletal muscle formation in the mature spinal cord. Gene expression profiling indicated that PAX3-FKHR expression in the developing neural tube induces a myogenic pattern of gene expression at the expense of the normal neurogenic program. Somite defects in PAX3-FKHR transgenic animals resulted in skeletal malformations that included rib fusions and mis-attachments. As opposed to the neural tube defects, the severity of the rib phenotype was rescued by reducing Pax3 levels through mating with Splotch mice. Embryos from the transgenic line expressing the highest levels of PAX3-FKHR had severe neural tube defects, including exencephaly, and almost half of the embryos died between gestational ages E13.5-E15.5. Nearly all of the embryos that survived to term died after birth due to severe spina bifida, rather than the absence of a muscular diaphragm. These studies reveal a prominent role for PAX3-FKHR in disrupting Pax3 functions and in deregulating skeletal muscle development, suggesting that this fusion protein plays a critical role in the pathogenesis of alveolar RMS by influencing the commitment and differentiation of the myogenic cell lineage.

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PubMed2006

YB-1 is important for an early stage embryonic development: neural tube formation and cell proliferation.

The eukaryotic Y-box-binding protein-1 (YB-1) is involved in the transcriptional and translational control of many biological processes, including cell proliferation. In clinical studies, the cellular level of YB-1 closely correlates with tumor growth and prognosis. To understand the role of YB-1 in vivo, especially in the developmental process, we generated YB-1 knock-out mice, which are embryonic lethal and exhibit exencephaly associated with abnormal patterns of cell proliferation within the neuroepithelium. beta-Actin expression and F-actin formation were reduced in the YB-1 null embryo and YB-1(-/-) mouse embryonic fibroblasts, suggesting that the neural tube defect is caused by abnormal cell morphology and actin assembly within the neuroepithelium. Fibroblasts derived from YB-1(-/-) embryos demonstrated reduced growth and cell density. A colony formation assay showed that YB-1(-/-) mouse embryonic fibroblasts failed to undergo morphological transformation and remained contact-inhibited in culture. These results demonstrate that YB-1 is involved in early mouse development, including neural tube closure and cell proliferation.

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PubMed1996

Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development.

Notch genes encode receptors for a signaling pathway that regulates neurogenesis. The DSL (Delta/Serrate/lag-2) genes encode ligands that bind and activate Notch. In situ hybridization was used to determine the spatiotemporal expression of Notch1, Notch2, and Notch3, and the DSL ligands, Jagged and Delta 1, in an effort to identify potential ligand-receptor pairs that function during development of the rat nervous system. Here we describe both distinct and overlapping expression patterns for these genes in neural progenitors that form both the central and the peripheral nervous systems. The punctate expression patterns we detected for Jagged and Delta 1 are consistent with their role in mediating lateral inhibition, a process proposed to regulate neural determination. Furthermore, within the ventricular zone of the neural tube and retina, Jagged and Delta 1 were expressed in complementary regions, suggesting that different DSL-Notch combinations may direct the development of distinct neural subtypes.

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PubMed1995

PGP9.5, a ubiquitin C-terminal hydrolase; pattern of mRNA and protein expression during neural development in the mouse.

PGP9.5 is a neurone and neuro-endocrine specific ubiquitin carboxyl terminal hydrolase estimated to form 1-2% of total brain protein. We have examined the temporal and spatial distribution of PGP9.5 mRNA and protein in the developing mouse embryo. These studies show that PGP9.5 is present at high levels in all differentiated neurones throughout the central and peripheral nervous systems at all stages of development. The mRNA is detected in the neural tube 1 day prior to the protein and before neuronal differentiation is underway. Both mRNA and protein are present during the initial appearance of motor and sensory neurones, prior to their peak production. PGP9.5 immunoreactivity was detected using microwave pretreatment of sections in order to unmask epitopes. In general unmasking led to an overall enhancement of immunoreactivity although in some sites, for example the dorsal root and cranial nerve ganglia and the bundle of His, there was evidence for anatomical variation in the distribution of masked versus unmasked protein. The very early expression of PGP9.5 suggests that there is a role for ubiquitin hydrolases in the differentiation of neurone precursors as well as in the differentiated neurone.

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PubMed1991

Control of dorsoventral pattern in vertebrate neural development: induction and polarizing properties of the floor plate.

Distinct classes of neural cells differentiate at specific locations within the embryonic vertebrate nervous system. To define the cellular mechanisms that control the identity and pattern of neural cells we have used a combination of functional assays and antigenic markers to examine the differentiation of cells in the developing spinal cord and hindbrain in vivo and in vitro. Our results suggest that a critical step in the dorsoventral patterning of the embryonic CNS is the differentiation of a specialized group of midline neural cells, termed the floor plate, in response to local inductive signals from the underlying notochord. The floor plate and notochord appear to control the pattern of cell types that appear along the dorsoventral axis of the neural tube. The fate of neuroepithelial cells in the ventral neural tube may be defined by cell position with respect to the ventral midline and controlled by polarizing signals that originate from the floor plate and notochord.

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PubMed1996

The murine homeobox gene Msx-3 shows highly restricted expression in the developing neural tube.

The mouse homeobox-genes Msx-1 and Msx-2 are expressed in several areas of the developing embryo, including the neural tube, neural crest, facial processes and limb buds. Here we report the characterisation of a third mouse Msx gene, which we designate Msx-3. The embryonic expression of Msx-3 was found to differ from that of Msx-1 and -2 in that it was confined to the dorsal neural tube. In embryos with 5-8 somites a segmental pattern of expression was observed in the hindbrain, with rhombomeres 3 and 5 lacking Msx-3 while other rhombomeres expressed Msx-3. This pattern was transient, however, such that in embryos with 18 or more somites expression was continuous throughout the dorsal hindbrain and anterior dorsal spinal cord. Differentiation of dorsal cell types in the neural tube can be induced by addition of members of the Tgf-beta family. Additionally, Msx-1 and -2 have been shown to be activated by addition of the Tgf-beta family member Bmp-4. To determine if Bmp-4 could activate Msx-3, we incubated embryonic hindbrain explants with exogenous Bmp-4. The dorsal expression of Msx-3 was seen to expand into more ventral regions of the neurectoderm in Bmp-4-treated cultures, implying that Bmp-4 may be able to mimic an in vivo signal that induces Msx-3.

Amino Acid Sequence↗
PubMed2003

Mosaic evolution of neural development in anurans: acceleration of spinal cord development in the direct developing frog Eleutherodactylus coqui.

Previous studies have shown that spinal cord development in direct developing frogs of the genus Eleutherodactylus, which have evolutionarily lost the tadpole stage, differs from that in biphasically developing anurans (with the larval and the adult stage separated by metamorphosis). The present study of spinal cord development in Eleutherodactylus coqui provides additional information about neurogenesis, neuronal differentiation and growth analyzed by immunostaining for proliferating cell nuclear antigen (PCNA), in situ hybridization for NeuroD, and morphometric measurements in various developmental stages. Furthermore, spinal cord development in the frogs Discoglossus pictus, Xenopus laevis, and Physalaemus pustulosus, which belong to different anuran families but all exhibit biphasic development, was similarly analyzed. This comparative analysis allows inference of the ancestral anuran pattern of spinal cord development and how it has been modified during the evolution of Eleutherodactylus. All biphasically developing frogs analyzed share a similar pattern of spinal cord development, suggesting that this is ancestral for anurans: after neural tube closure, levels of proliferation and neurogenesis in the spinal cord were low throughout embryogenesis until they were upregulated drastically at early larval stages followed by development of the lateral motor columns. In contrast, no such quiescent embryonic period exists in E. coqui, where rapid growth, high levels of proliferation and neurogenesis, and early formation of lateral motor columns occur shortly after neural tube closure, while other parts of the central nervous system develop more slowly. Thus, spinal cord development has been accelerated during the evolution of Eleutherodactylus relative to the development of other parts of the central nervous system, probably related to the precocious development of limbs in this lineage.

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PubMed2002

Expression and characterization of the Drosophila X11-like/Mint protein during neural development.

The X11-like (X11L) protein was originally isolated as a protein bound to the cytoplasmic domain of the beta-amyloid precursor protein (APP), which is associated with Alzheimer's disease. In mammals, X11L is believed to play an important role in the regulation of APP metabolism. Here we isolated and characterized the Drosophila X11L (dX11L) protein, also may be referred to this protein as Drosophila Mint (dMint), Lin 10 (dLin10) or X11 (dX11), is thought to be expressed in neuronal tissues from late embryonic through to the adult stages of the fly. The phosphotyrosine interaction domain of dX11L interacts with the cytoplasmic domain of the Drosophila amyloid precursor protein-like (APPL) similar to the way human X11L (hX11L) interacts with APP. Overexpression of dX11L on post-mitotic neurons had a lethal effect on flies and, when it was localized to the eye imaginal disc, disruption of compound eye morphology due to enhanced apoptosis of neuronal cells was observed. Overexpression of hX11L and the PDZ domain of dX11L resulted in identical eye phenotypes. The PDZ domain is highly conserved between Drosophila and human, and appears to be responsible for this phenotype. Our findings suggest that the X11L family may be involved with the regulation of apoptosis during neural cell development and that aberrant X11L function could be contribute in this way to the neuronal degeneration observed in Alzheimer's disease.

Amino Acid Sequence↗
PubMed1989

A multifaceted approach to neural development.

The developing compound eye of the fruit fly, Drosophila offers notable advantages for a study of neural differentiation. It is a sensitive amplifier of a simple neural module; each eye is an approximately 700-fold repetition of the unit eye or ommatidium, which is a precise, stereotyped assembly of photoreceptors and accessory cells. The eye develops in a monolayer epithelium, which greatly reduces the complexities of cell-cell interactions often encountered in CNS development, and has permitted a detailed, cell-by-cell description of cell behavior during ommatidial development. Finally, the foundation of fly genetics permits a mutational analysis of eye development and the advanced molecular genetics of Drosophila allows close scrutiny of genes of interest. A recent convergence of cellular, genetic and molecular studies of ommatidial development suggests a model for neural differentiation in the fly eye.

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PubMed2000

The RET receptor tyrosine kinase: activation, signalling and significance in neural development and disease.

The RET receptor tyrosine kinase was first identified in a screen for human oncogenes and has subsequently been linked to several human syndromes: Hirschprung's disease, multiple endocrine neoplasia types 2A and 2B and familial thyroid carcinoma. Interestingly, all of the tissues affected by mutations in RET are derived from the neural crest during development. RET transduces a signal following activation by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN), artemin (ART) and persephin (PSP). To activate RET they form a tripartite complex with RET and a member of a family of four extracellular, GPI-linked alpha receptors (GFR alpha 1-4). Specificity is achieved by each GFR alpha binding only one member of the GDNF family with high affinity. Current evidence indicates that signal transduction by RET activates several second messenger systems including the PLC gamma, Ras, JNK and inositol phosphate pathways. Targeted mutagenesis in transgenic mice has shown that Ret, GFR alpha 1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease. We describe experiments in chick neural crest cells which provide evidence for the normal function of RET and the basis of the defect in Hirschsprung's disease.

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PubMed1987

Localization of glycoconjugates recognized by the HNK-1 antibody in mouse and chick embryos during early neural development.

The monoclonal antibody HNK-1 recognizes a carbohydrate epitope present on a host of glycoconjugates which include the glycoproteins neural cell adhesion molecules (N-CAM) myelin-associated glycoprotein and ependymins, and two glycolipids. Other antibodies, including NC-1, L2 and IgM paraproteins from neuropathy patients share similar binding specificity to the same or related sulfated glucuronyl-containing antigen (SGA). To further investigate its possible significance in early development, the distribution of SGA was studied in the head region of early developing chick (S13-S18) and mouse (E8.5-E11.5) embryos by immunocytochemistry. A striking species difference was found in the apparent distribution of immunodetectable SGA. In chick, migrating neural crest cells and their related cell types were heavily stained by HNK-1; whereas no stain was detectable on mouse neural crest cells at comparable stages, except perhaps in a restricted area adjacent to the otic placode and immediately adjacent to the neural tube. Within the developing CNS, the distribution of SGA was similar in both species. It was first expressed on neuroepithelial cells prior to axonal outgrowth, and was distributed in a continuous zone along the entire lateral walls of the early neural tube. Little or no SGA was detectable along most of the floor and roof plates. SGA appeared during this same period in the lateral basal lamina and within the adjacent mesenchyme and nearby cells. SGA was particularly evident on neuroepithelial endfeet at this stage. Early developing longitudinal axons were subsequently found to grow in association with the endfeet of SGA-positive neuroepithelial cells. These findings, in conjunction with previous studies, suggest that SGA is associated as a marker, and perhaps functionally, with the organization of early neuronal settling and axonal growth patterns within the developing vertebrate CNS.

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PubMed1996

Regulation of patched by sonic hedgehog in the developing neural tube.

Ventral cell fates in the central nervous system are induced by Sonic hedgehog, a homolog of hedgehog, a secreted Drosophila protein. In the central nervous system, Sonic hedgehog has been identified as the signal inducing floor plate, motor neurons, and dopaminergic neurons. Sonic hedgehog is also involved in the induction of ventral cell type in the developing somites. ptc is a key gene in the Drosophila hedgehog signaling pathway where it is involved in transducing the hedgehog signal and is also a transcriptional target of the signal. PTC, a vertebrate homolog of this Drosophila gene, is genetically downstream of Sonic hedgehog (Shh) in the limb bud. We analyze PTC expression during chicken neural and somite development and find it expressed in all regions of these tissues known to be responsive to Sonic hedgehog signal. As in the limb bud, ectopic expression of Sonic hedgehog leads to ectopic induction of PTC in the neural tube and paraxial mesoderm. This conservation of regulation allows us to use PTC as a marker for Sonic hedgehog response. The pattern of PTC expression suggests that Sonic hedgehog may play an inductive role in more dorsal regions of the neural tube than have been previously demonstrated. Examination of the pattern of PTC expression also suggests that PTC may act in a negative feedback loop to attenuate hedgehog signaling.

Animals↗
PubMed1996

Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development.

HGF-like protein (HLP), also known as macrophage stimulating protein, is a ligand for Ron receptor tyrosine kinase, a member of the c-Met/hepatocyte growth factor receptor family. We cloned a Xenopus homologue of the Ron/HLP receptor (Xron) and HLP (Xhlp) and analyzed temporal and spatial expressions. Both Xron and Xhlp mRNA were detected in Xenopus embryos at the cleavage stage, as maternally pooled RNA. Zygotic expression of Xron mRNA was seen in early embryos during midblastula and neurula (stage 22), while Xhlp was evident during midblastula and early tadpole (stage 40). Xron mRNA was localized in the most frontal region of the neural fold and peripheral regions of the neural plate, while Xhlp mRNA was seen in midline of the neural plate (notoplate) and the most frontal regions of the neural fold in early neurula. Thus, functional coupling between Ron receptor tyrosine kinase and HLP may have an important role in development of embryonic neural tissue in Xenopus laevis.

Amino Acid Sequence↗
PubMed2002

Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart.

Caspase-8 plays the role of initiator in the caspase cascade and is a key molecule in death receptor-induced apoptotic pathways. To investigate the physiological roles of caspase-8 in vivo, we have generated caspase-8-deficient mice by gene targeting. The first signs of abnormality in homozygous mutant embryos were observed in extraembryonic tissue, the yolk sac. By embryonic day (E) 10.5, the yolk sac vasculature had begun to form inappropriately, and subsequently the mutant embryos displayed a variety of defects in the developing heart and neural tube. As a result, all mutant embryos died at E11.5. Importantly, homozygous mutant neural and heart defects were rescued by ex vivo whole-embryo culture during E10.5-E11.5, suggesting that these defects are most likely secondary to a lack of physiological caspase-8 activity. Taken together, these results suggest that caspase-8 is indispensable for embryonic development.

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PubMed2000

Endocytosis and transcytosis in growing astrocytes in primary culture. Possible implications in neural development.

Endocytosis constitutes an essential process in the regulation of the expression of cell surface molecules and receptors and, therefore, could participate in the neural-glial interactions occurring during brain development. However, the relationship between endocytic pathways in astroglial cells under physiological and pathological conditions remains poorly understood. We analyzed the endocytosis and transcytosis processes in growing astrocytes and the possible effect of ethanol on these processes. Evidence demonstrates that ethanol affects endocytosis in the liver and we showed that ethanol exposure during brain development alters astroglial development changing plasma membrane receptors and surface glycoprotein composition. To study these processes we use several markers for receptor-mediated endocytosis, fluid phase endocytosis and non-specific endocytosis. These markers were labeled for fluorescence microscopy and electron microscopy. 125I-BSA was used to study the effect of ethanol on the internalization and recycling of this macromolecule. The distribution of several proteins involved in endocytosis (caveolin, clathrin, rab5 and beta-COP) was analyzed using immunofluorescence, immunoelectron microscopy and immunoblotting. Our results indicate that growing astrocytes have a developed endocytic system mainly composed of caveolae, clathrin coated pits and vesicles, tubulo-vesicular and spheric endosomes, multivesicular bodies and lysosomes. Ethanol exposure induces a fragmentation of tubular endosomes, decreases the internalization of 125I-BSA, alters the processing of internalized BSA, and decreases the levels of caveolin, clathrin, rab5 and beta-COP. These results indicate that ethanol alters the endocytosis and transcytosis processes and impairs protein trafficking in astrocytes, which could perturb astrocyte surface expression of molecules involved in neuronal migration and maturation during brain development.

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PubMed2000

Neurotransmitters and gap junctions in developing neural circuits.

A growing body of evidence suggests that highly correlated, spontaneous neural activity plays an important role in shaping connections in the developing nervous system prior to the maturation of sensory afferents. In this article we discuss the mechanisms involved in the generation and the regulation of spontaneous activity patterns in the developing retina and the developing neocortex. Spontaneous activity in the developing retina propagates across the ganglion cell layer as waves of action potentials and drives rhythmic increases in intracellular calcium in retinal neurons. Retinal waves are mediated by a combination of chemical synaptic transmission and gap junctions, and the circuitry responsible for generating retinal waves changes with age and between species. In the developing cortex, spontaneous calcium elevations propagate across clusters of cortical neurons called domains. Cortical domains are generated by a regenerative mechanism involving second messenger diffusion through gap junctions and subsequent calcium release from internal stores. The neocortical gap junction system is regulated by glutamate-triggered second messenger systems as well as neuromodulatory transmitters, suggesting extensive interactions between synaptic transmission and information flow through gap junctions. The interaction between gap junctions and chemical synaptic transmission observed in these developing networks represent a powerful mechanism by which activity across large groups of neurons can be correlated.

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