Neocortical neurons: where do they come from?
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Animals↗
Biomedical subjects
A Lumsden
Publications and source records attributed to A Lumsden.
Identification of dysfunctional endothelial cells over vascular lesions in the non-human primate.
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Actins↗
Segregation of rhombomeres by differential chemoaffinity.
The developing hindbrain is transiently subdivided into structural repeat units, rhombomeres, whose formation is matched by both differential regulatory gene expression and a metameric pattern of early neuronal differentiation and axogenesis. Individual rhombomeres are polyclonal cell lineage restriction units; once defined by transverse interrhombomere interfaces, cells are confined within the territory of a single rhombomere. In order to assess the relevance of this restriction to hindbrain development. It is necessary to understand the underlying mechanism. One possibility is that cells of adjacent rhombomeres acquire differential affinities or adhesive properties. To explore this possibility, we isolated rhombomere cells, mixed them together in short-term aggregation cultures, and assessed the composition of the resulting aggregates. We found that rhombomeres do differ in their affinity: cells from even-numbered rhombomeres sort out from cells of odd-numbered rhombomeres. They also segregate from cells of other even-numbered rhombomeres but to a much lesser extent. This selective cell affinity operates from the time of rhombomere formation until late stages in development. The region-specific segregation was abolished when Ca(2+)-dependent adhesion molecules were inactivated but not when Ca(2+)-independent adhesion molecules were inactivated. These findings suggest that distinct cell affinity restricts cell mixing between adjacent rhombomeres and may be involved in establishing the series of discrete compartments, thereby maintaining anteroposterior positional information during hindbrain development. These results support a general role for cell adhesion molecules in subdividing CNS territories.
Animals↗
Safety, feasibility, and early efficacy of subfascial endoscopic perforator surgery: a preliminary report from the North American registry.
PURPOSE: The North American Subfascial Endoscopic Perforator Surgery (NASEPS) Registry was established to evaluate the safety, feasibility, and efficacy of minimally invasive endoscopic Linton operations for treatment of chronic venous insufficiency. METHODS: Retrospective analysis was performed on the clinical data of 151 patients who underwent attempt at 158 SEPS in 17 medical centers in the United States and Canada between June 1993 and February 1996. RESULTS: SEPS was completed on 155 limbs of 148 patients, 81 male and 67 female (mean age, 56 years; range, 27 to 87 years). Three procedures were aborted. Seven patients had bilateral procedures (data from one limb were analyzed). One hundred four limbs (70%) had active ulcers, and 22 (15%) had healed ulcers. A single endoscopic port without insufflation was used in 66 procedures (45%) and laparoscopic instrumentation, with two or three ports, in 82 (55%), with CO2 insufflation in 78 (53%). A tourniquet was used on 112 patients (76%). Concomitant venous procedures were performed in 106 patients (72%; saphenous stripping in 71, high ligation in 17, varicosity avulsion in 85). No early deaths or thromboembolism occurred. Complications included wound infections (9), superficial thrombophlebitis (5), cellulitis (4), and saphenous neuralgia (10). Seven patients with wound infection had open ulcers; nine of 10 with neuralgia had concomitant procedures. A roll-on tourniquet caused skin necrosis in one patient. The clinical score improved from 9.4 to 2.9 after surgery (p < 0.0001). Mean follow-up was 5.4 months; 31 patients had > or = 6 months follow-up. Ulcers healed in 88% (75 of 85); recurrence or new ulcer was reported in 3% (4 of 120). CONCLUSIONS: The SEPS modified Linton operation appears safe, with no postoperative deaths or early thromboembolism. Wound infection after SEPS remains important. Early results indicate rapid ulcer healing. Prospective evaluation of long-term results is warranted.
Adult↗
Development. The end of the beginning?
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Animals↗
Organization and development of facial motor neurons in the kreisler mutant mouse.
The adult facial nerve contains the axons from two populations of efferent neurons. First, the branchiomotor efferent neurons that innervate the muscles of the second arch. These neurons project out of the hindbrain in the motor root and form the facial motor nuclei. Second, the preganglionic efferent neurons that innervate the submandibular and pterygopalatine ganglia. These neurons project from the hindbrain via the intermediate nerve and form the superior salivatory nucleus. The motor neurons of the facial nerve are known to originate within rhombomeres 4 and 5. In the kreisler mouse mutant there is a specific disruption of the hindbrain rhombomeres 5 and 6 appear to be absent. To investigate changes in the organization of the facial motor neurons in this mutant, we have used lipophilic dyes to trace the facial motor components both retrogradely and anterogradely. As expected, facial motor neurons are missing from rhombomere 5 in this mutant. In addition, the loss of these neurons correlates with the specific loss of the superior salivatory nucleus. In contrast, the branchiomeric neurons, that originate in rhombomere 4, appear to develop normally. This includes the caudal migration of their cell bodies forming the genu of the facial nerve. Our studies confirm that rhombomeres are critical to hindbrain development and that they are the fundamental unit at which motor neurons are specified.
Animals↗
Coordination of early neural tube development by BDNF/trkB.
Neurotrophins signal through members of the trk family of tyrosine kinase receptors and are known to regulate several neuronal properties. Although initially characterized by their ability to prevent naturally occurring cell death of subsets of neurons during development, neurotrophins can also regulate the proliferation and differentiation of precursor cells. Here we report a novel involvement of neurotrophins in early development of the neural tube. We demonstrate that a functional trkB receptor is expressed by motor neuron progenitors in the ventral neural tube and that treatment of ventral neural tube explants with the trkB ligand Brain-Derived Neurotrophic Factor (BDNF) leads to a significant increase in the number of motor neurons. The only BDNF expression detectable at this stage is by a subset of ventrally projecting interneurons in the dorsal neural tube; ablating this region in vivo leads to a reduction of motor neuron numbers. This loss can be prevented by simultaneous treatment with BDNF. We propose that BDNF produced by dorsal interneurons stimulates proliferation and/or differentiation of motor neuron progenitors after anterograde axonal transport and release in proximity to the trkB-expressing motor neuron precursors, thereby coordinating development between dorsal and ventral regions of the neural tube.
Animals↗
The role of Engrailed in establishing the dorsoventral axis of the chick limb.
Expression and mutation analyses in mice suggest that the homeobox-containing gene Engrailed (En) plays a role in dorsoventral patterning of the limb. During the initial stages of limb bud outgrowth, En-1 mRNA and protein are uniformly distributed throughout the ventral limb bud ectoderm. Limbs of En-1(-/-) mice display a double dorsal phenotype suggesting that normal expression of En-1 in the ventral ectoderm is required to establish and/or maintain ventral limb characteristics. Loss of En-1 function also results in ventral expansion of the apical ectodermal ridge (AER), suggesting that En-1 is also required for proper formation of the AER. To further investigate the role En plays in dorsoventral patterning and AER formation, we have used the replication competent retroviral vector, RCAS, to mis-express mouse En-1 in the early chick limb bud. We show that ectopic En-1 expression in dorsal ectoderm is sufficient to repress the endogenous expression of the dorsal ectodermal marker Wnt7a, with a resultant decrease in Lmx1 expression in underlying dorsal mesenchyme. Furthermore, the AER is disrupted morphologically and the expression patterns of the AER signalling molecules Fgf-8 and Fgf-4 are altered. Consistent with recent evidence that there is a reciprocal interaction between signalling molecules in the dorsal ectoderm, AER, and zone of polarising activity (ZPA), loss of Wnt7a, Fgf-8 and Fgf-4 expression leads to a decrease in expression of the signalling molecule Shh in the ZPA. These results strongly support the idea that, in its normal domain of expression, En-1 represses Wnt7a-mediated dorsal differentiation by limiting the expression of Wnt7a to the dorsal ectoderm. Furthermore, our results provide additional evidence that En-1 is involved in AER formation and suggest that En-1 may act to define ventral ectodermal identity.
Alpharetrovirus↗
Role of Hoxa-2 in axon pathfinding and rostral hindbrain patterning.
Segmentation plays an important role in neuronal diversification and organisation in the developing hindbrain. For instance, cranial nerve branchiomotor nuclei are organised segmentally within the basal plates of successive pairs of rhombomeres. To reach their targets, motor axons follow highly stereotyped pathways exiting the hindbrain only via specific exit points in the even-numbered rhombomeres. Hox genes are good candidates for controlling this pathfinding, since they are segmentally expressed and involved in rhombomeric patterning. Here we report that in Hoxa-2(-/-) embryos, the segmental identities of rhombomere (r) 2 and r3 are molecularly as well as anatomically altered. Cellular analysis by retrograde dye labelling reveals that r2 and r3 trigeminal motor axons turn caudally and exit the hindbrain from the r4 facial nerve exit point and not from their normal exit point in r2. Furthermore, dorsal r2-r3 patterning is affected, with loss of cochlear nuclei and enlargement of the lateral part of the cerebellum. These results point to a novel role for Hoxa-2 in the control of r2-r3 motor axon guidance, and also suggest that its absence may lead to homeotic changes in the alar plates of these rhombomeres.
Animals↗
Control of dorsoventral pattern in the chick paraxial mesoderm.
The most profound feature of the mature vertebrate somite is its organisation into dorsal dermomyotome, intermediate myotome and ventral sclerotome. We analysed the role of potential signalling structures in this dorsoventral pattern by ablating them or transplanting them to ectopic locations in chick embryos. Our data suggest that the somite represents a naive tissue, entirely depending on external cues for its dorsoventral organisation. Dorsalisation by signals from dorsal neural tube and surface ectoderm stimulates the development of the dermomyotome. Likewise, signals from notochord and floor plate ventralise the somite, at high levels overriding any dorsal information and inducing the sclerotome. The dorsalising factors and lower levels of the ventralising factors act in concert to induce the myotome. Finally, the paraxial mesoderm intrinsically controls its competence to respond to the external inducers.
Animals↗
Segmental and neuronal architecture of the hindbrain of Krox-20 mouse mutants.
The vertebrate hindbrain is transiently segmented during its early development with the formation of reiterated bulges, the rhombomeres (r). The Krox-20 gene, which encodes a zinc finger transcription factor, has been shown previously to be implicated in the maintenance of r3 and r5 (Schneider-Maunoury, S., Topilko, P., Seitanidou, T., Levi, G., Cohen-Tannoudji, M., Pournin, S., Babinet, C. and Charnay, P. (1993) Cell 75, 1199-1214; Swiatek, P. J. and Gridley, T. (1993) Genes Dev. 7, 2071-2084. However, it was not clear from these analyses how extensive the deletion of r3 and r5 was and whether the overall segmentation and internal architecture of the hindbrain was affected. We have now reinvestigated these issues by analysis of rhombomere boundaries, using both morphological and molecular markers, and of the fate of specific motor neuron populations, using retrograde and anterograde carbocyanine dye tracing. We conclude that r3 and r5 and their derivatives are completely eliminated in Krox-20(-/-) embryos while overall hindbrain segmentation is maintained. In addition, we show that the disappearance of these territories has important consequences for even-numbered rhombomeres as well, in particular on axonal navigation: (i) a population of r6 motoneurons, presumably normally fated to join the glossopharyngeal nerve, has its axons misrouted toward the facial exit point in r4; (ii) the trigeminal motor axons are also misrouted, presumably because of the proximity of the trigeminal and facial exit points. They fasciculate with facial axons outside the neural tube and enter the second branchial arch instead of the first arch. This navigational error could explain the disappearance, at around 17.5 dpc, of the trigeminal motor nucleus in Krox-20(-/-) embryos by inadequate supply of essential, possibly arch-specific survival factors.
Animals↗
Patterning the vertebrate neuraxis.
Neuraxial patterning is a continuous process that extends over a protracted period of development. During gastrulation a crude anteroposterior pattern, detectable by molecular markers, is conferred on the neuroectoderm by signals from the endomesoderm that are largely inseparable from those of neural induction itself. This coarse-grained pattern is subsequently reinforced and refined by diverse, locally acting mechanisms. Segmentation and long-range signaling from organizing centers are prominent among the emerging principles governing regional pattern.
Animals↗
Rostral optic tectum acquires caudal characteristics following ectopic engrailed expression.
BACKGROUND: Expression of the homeobox-containing gene Engrailed (En) in an increasing rostral-to-caudal gradient in the dorsal mesencephalon is the earliest known marker for polarity of the chick optic tectum. In heterotopic transplantation experiments, En protein expression correlates well with the subsequent gradient of cytoarchitecture as well as the pattern of retinotectal projections. The En gradient also correlates with the expression of two putative retinal axon-guidance molecules, RAGS and ELF-1, which are Eph-like receptor tyrosine kinase ligands that may function in the establishment of retinotopic projections by excluding temporal axons from the caudal tectum. RESULTS: To examine the function of En in determining tectal polarity, we used the replication-competent retroviral vector RCAS to misexpress mouse En-1 throughout the chick tectal primordium. Our results show that the rostral portion of the tectum adopts a caudal phenotype: the gradient of cytoarchitectonic differentiation is abolished, and the molecular markers RAGS and ELF-1 are strongly expressed rostrally. In addition, cell membranes from rostral tectum of RCAS En-1-infected embryos preferentially repel temporal axons in in vitro membrane stripe assays. CONCLUSIONS: These results are consistent with a role for En in determining rostrocaudal polarity of the developing tectum. The demonstration that both RAGS and ELF-1 are upregulated following En misexpression provides a molecular basis for understanding the previous observation, also based on retrovirus-mediated En misexpression, that nasal axons form ectopic connections in rostral tectum, from which temporal axons are excluded.
Animals↗
Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog.
Near the floor plate of the embryonic neural tube there is a group of neuroepithelial precursor cells that are specialized for production of the oligodendrocyte lineage. We performed experiments to test whether specification of these neuroepithelial oligodendrocyte precursors, like other ventral neural cell types, depends on signals from the notochord and/or floor plate. We analyzed heterozygous Danforth's short tail (Sd/+) mutant mice, which lack a notochord and floor plate in caudal regions of the neural tube, and found that oligodendrocyte precursors did not appear at the ventricular surface where there was no floor plate. Moreover, oligodendrocytes did not develop in explant cultures of Sd/+ spinal cord in the absence of a floor plate. When a second notochord was grafted into an ectopic position dorsolateral to the endogenous notochord of a chicken embryo, an additional floor plate was induced along with an ectopic focus of oligodendrocyte precursors at the ventricular surface. Oligodendrocytes developed in explants of intermediate neural tube only when they were cocultured with fragments of notochord or in the presence of purified Sonic hedgehog (Shh) protein. Thus, signals from the notochord/floor plate, possibly involving Shh, are necessary and sufficient to induce the development of ventrally derived oligodendroglia. These signals appear to act by specifying the future fate(s) of neuroepithelial cells at the ventricular surface rather than by influencing the proliferation or differentiation of prespecified progenitor cells in the parenchyma of the cord.
Animals↗
The role of FGF-3 in early inner ear development: an analysis in normal and kreisler mutant mice.
The development of the otic placode is believed to depend on an inductive signal from the adjacent hindbrain. A candidate for this signal is FGF-3 (Int-2), which is expressed in the hindbrain adjacent to the future ear in rhombomeres 5 and 6 (r5 and r6). However, in vitro tests (Represa et al. (1991), Nature 353, 561-563) conflict with findings from FGF-3 knockout mice (Mansour et al. (1993), Development 117, 13-28). The former suggest that FGF-3 from the hindbrain is required to induce formation of the otocyst, while the latter imply that FGF-3 is required only in the later process of otocyst differentiation. We find that in normal embryos at early stages the gene is expressed not only in r5 and r6, but also in most of the hindbrain anterior to this and in the head ectoderm in the prospective otic placode region. In kreisler mutant embryos, however, there is no heightened expression in r5 and r6, but the early patch of expression in the prospective otic placode ectoderm is still seen and the otic vesicle still forms at nearly the normal place. Subsequent malformations of the inner ear in kreisler and in FGF-3 knockout mice are similar, involving failure of the development of the endolymphatic appendage. These findings argue that FGF-3 is not required as an inductive signal for invagination of the otic placode to form a vesicle, whose future site is already marked out independently of any localized FGF-3 signal from r5 and r6. FGF-3 does, however, appear to be required for a correct pattern of differentiation within the vesicle.
Animals↗
Neural crest apoptosis and the establishment of craniofacial pattern: an honorable death.
During development of the vertebrate head neural crest cells emigrate from the hindbrain and populate the branchial arches, giving rise to distinct skeletal elements and muscle connective tissues in each arch. The production of neural crest from the hindbrain is discontinuous and crest cells destined for different arches, carrying different positional cues, are separated by regions of apoptosis centered on rhombomeres (r) 3 and r5. This cell death program is under the interactive control of the neighboring hindbrain segments. Both r3 and r5 produce large numbers of crest cells when freed from their flanking rhombomere, but when conjoined with their neighbor the cell death program is restored. Two key components of this program are Bmp 4 and msx-2, both of which are expressed in the apoptotic foci of r3 and r5 and which are also regulated by neighbor interactions. Importantly, the addition of recombinant Bmp 4 to isolated cultures of r3 and r5 induces the expression of Bmp 4 and msx-2 and restores the cell death program. This early neural crest segregation is maintained during development and it has profound effects upon the final craniofacial pattern. Even though crest cells from different axial origins will contribute to compound skeletal elements, these distinct populations do not intermingle. Furthermore head muscle connective tissues are exclusively anchored to skeletal domains arising from neural crest from the same axial level. Thus the discontinuous production of neural crest sculpts the crest into nonmixing streams and consequently ensures the fidelity of patterning.
Animals↗
Selective adhesion of cells from different telencephalic regions.
We asked whether specifications of different regions of the rodent and avian telencephalon during development involved the acquisition of differential adhesive properties. Cells from different regions were aggregated in a short-term aggregation assay, and their segregation was analyzed. Both neurons and precursor cells from cortex segregate from striatal cells at early, but not later, stages, whereas cells from rodent neocortex and hippocampus segregated only during later stages. Segregation was abolished when Ca2+-dependent but not Ca2+-independent adhesion molecules were selectively removed. Thus, selective adhesion appears to be a conserved mechanism that restricts cellular mixing and might serve to maintain positional information during forebrain development. A candidate for mediating the Ca2+-dependent segregation is the CD15 (Lewis(x)) carbohydrate epitope, which is selectively expressed by mammalian cortex but not striatum.
Animals↗
Cranial motor axons respond differently to the floor plate and sensory ganglia in collagen gel co-cultures.
Within the developing chick hindbrain, motor neurons differentiate in columns on either side of the ventral midline floor plate. Along the rostrocaudal axis, populations of motor neurons are organized segmentally with the trigeminal (V) and facial (VII) nuclei occupying successive pairs of rhombomeres. To reach their targets, motor axons follow stereotyped pathways. Branchiomotor and visceral motor axons of the Vth and VIIth nerves first project in a dorsal (lateral) direction away from the floor plate and towards the nerve exit point located in the alar plate of the even-numbered rhombomere of the pair. Having exited the hindbrain, axons grow in association with the cranial sensory ganglia before branchiomotor axons enter the branchial arches. We have investigated some of the factors that might guide cranial motor axons using a three-dimensional collagen gel culture system. When explants of hindbrain basal plate containing trigeminal or facial motor neurons were co-cultured with floor plate explants, axon outgrowth from the side facing the floor plate was inhibited in a manner consistent with chemorepulsion. When basal plate explants that contained an exit point were cultured alone, motor axons grew to the exit point and then stopped. When basal plate explants were co-cultured with trigeminal ganglia, motor outgrowth was increased in comparison with that in control cultures, suggesting a trophic influence. The findings presented here indicate that motor pathways are elaborated due to a progression of signals to which the growth cones respond in sequence.
Animals↗