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Biomedical subjects

A Lumsden

Publications and source records attributed to A Lumsden.

At least 37 records · Page 2Linked to original sources
PubMed2000

The WNT antagonist cSFRP2 modulates programmed cell death in the developing hindbrain.

In the avian hindbrain, the loss of premigratory neural crest cells from rhombomeres 3 and 5 (r3, r5) through programmed cell death contributes to the patterning of emigrant crest cells into three discrete streams. Programmed cell death is induced by the upregulation of Bmp4 and Msx2 in r3 and r5. We show that cSFRP2, a WNT antagonist, is expressed in the even-numbered rhombomeres and that over-expression of cSfrp2 inhibits Bmp4 expression in r3 and r5, preventing programmed cell death. By contrast, depleting cSFRP2 function in r4 results in elevated levels of Msx2 expression and ectopic programmed cell death, as does overexpression of Wnt1. We propose that programmed cell death in the rhombencephalic neural crest is modulated by pre-patterned cSfrp2 expression and a WNT-BMP signalling loop.

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PubMed2000

Homeotic transformation of branchial arch identity after Hoxa2 overexpression.

Overexpression of Hoxa2 in the chick first branchial arch leads to a transformation of first arch cartilages, such as Meckel's and the quadrate, into second arch elements, such as the tongue skeleton. These duplicated elements are fused to the original in a similar manner to that seen in the Hoxa2 knockout, where the reverse transformation of second to first arch morphology is observed. This confirms the role of Hoxa2 as a selector gene specifying second arch fate. When first arch neural crest alone is targeted, first arch elements are lost, but the Hoxa2-expressing crest is unable to develop into second arch elements. This is not due to Hoxa2 preventing differentiation of cartilages. Upregulation of a second arch marker in the first arch, and homeotic transformation of cartilage elements is only produced after global Hoxa2 overexpression in the crest and the surrounding tissue. Thus, although the neural crest appears to contain some patterning information, it needs to read cues from the environment to form a coordinated pattern. Hoxa2 appears to exert its effect during differentiation of the cartilage elements in the branchial arches, rather than during crest migration, implying that pattern is determined quite late in development.

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PubMed1999

Homeotic transformation of rhombomere identity after localized Hoxb1 misexpression.

Segmentation of the hindbrain and branchial region is a conserved feature of head development, involving the nested expression of Hox genes. Although it is presumed that vertebrate Hox genes function as segment identifiers, responsible for mediating registration between elements of diverse embryonic origin, this assumption has remained untested. To assess this, retroviral misexpression was combined with orthotopic grafting in chick embryos to generate a mismatch in Hox coding between a specific rhombomere and its corresponding branchial arch. Rhombomere-restricted misexpression of a single gene, Hoxb1, resulted in the homeotic transformation of the rhombomere, revealed by reorganization of motor axon projections.

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PubMed1999

Distribution of neuregulin-1 (nrg1) and erbB4 transcripts in embryonic chick hindbrain.

Interrhombomeric signalling has a role in development of the chick hindbrain. We have examined the transcript distributions of neuregulin-1 (nrg1), a signalling molecule with effects on nervous system development, and of one of its receptors, erbB4. Expression patterns of these two molecules are, in contrast to the situation in mouse, not consistent with a role in interrhombomeric signalling, but are consistent with a role in signalling between dorsal and ventral territories within individual rhombomeres. Other areas of potential nrg1-erbB4 signalling are the cerebellum, the caudal rhombic lip, and dorsolateral mantle in the caudal hindbrain. nrg1 is additionally expressed in motor neurons and erbB4 in rostral rhombic lip plus a subset of rhombic lip derivatives. Both molecules are also expressed in other parts of the nervous system and in nonneuronal tissue. The expression data presented will facilitate interpretation of future functional studies on nrg1-erbB4 signalling during hindbrain development.

Amino Acid Sequence↗
PubMed1999

Expression of GATA-2 in the developing avian rhombencephalon.

Here we describe the expression pattern of GATA-2 in the developing chick hindbrain. We found that during the early period of neurogenesis this gene specifically labels a particular neuronal subtype, the contralateral vestibular-acoustic neurons of rhombomere 4, and that expression of this gene in these cells is transient. We also found that GATA-2 labels a broader territory of the ventral neural tube at later stages. As well as this hindbrain expression, we also describe expression of GATA-2 in the otic vesicle, oculomotor nucleus, third nerve and metanephros.

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PubMed1999

Segmental specification of GABAergic inhibition during development of hindbrain neural networks.

A primordial rhythm-generating neural network emerges during the segmental period of vertebrate hindbrain development, suggesting a common genetic basis to both the structure and network activity of the region. We show here that segmentation influenced a postsegmental developmental step by which a GABAergic rhythm generator was incorporated into the primordial network and increased rhythm frequency to near mature values. This process depended on specifications in r3 and r5 that controlled, on the basis of a two-segment repeat, later maturation of GABAergic inhibition.

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PubMed1999

Specification of distinct motor neuron identities by the singular activities of individual Hox genes.

Hox genes have been implicated in specifying positional values along the anteroposterior axis of the caudal central nervous system, but their nested and overlapping expression has complicated the understanding of how they confer specific neural identity. We have employed a direct gain-of-function approach using retroviral vectors to misexpress Hoxa2 and Hoxb1 outside of the normal Hox expression domains, thereby avoiding complications resulting from possible interactions with endogenous Hox genes. Misexpression of either Hoxa2 or Hoxb1 in the anteriormost hindbrain (rhombomere1, r1) leads to the generation of motor neurons in this territory, even though it is normally devoid of this cell type. These ectopic neurons have the specific identity of branchiomotor neurons and, in the case of Hoxb1-induced cells, their axons leave the hindbrain either by fasciculating with the resident cranial motor axons at isthmic (trochlear) or r2 (trigeminal) levels of the axis or via novel ectopic exit points in r1. Next, we have attempted to identify the precise branchiomotor subtypes that are generated after misexpression and our results suggest that the ectopic motor neurons generated following Hoxa2 misexpression are trigeminal-like, while those generated following Hoxb1 misexpression are facial-like. Our data demonstrate, therefore, that at least to a certain extent and for certain cell types, the singular activities of individual Hox genes (compared to a combinatorial mode of action, for example) are sufficient to impose on neuronal precursor cells the competence to generate distinctly specified cell types. Moreover, as these particular motor neuron subtypes are normally generated in the most anterior domains of Hoxa2 and Hoxb1 expression, respectively, our data support the idea that the main site of individual Hox gene action is in the anteriormost subdomain of their expression, consistent with the phenomenon of posterior dominance.

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PubMed1999

Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain.

Experiments involving tissue recombinations have implicated both early vertical and later planar signals in the specification and polarisation of the midbrain. Here we investigate the role of fibroblast growth factors in regulating these processes in the avian embryo. We show that Fgf4 is expressed in the notochord anterior to Hensen's node before transcripts for the earliest molecular marker of midbrain tissue in the avian embryo, En1, are detected. The presence of notochord is required for the expression of En1 in neural plate explants in vitro and FGF4 mimics this effect of notochord tissue. Subsequently, a second member of the fibroblast growth factor family, Fgf8, is expressed in the isthmus in a manner consistent with it providing a polarising signal for the developing midbrain. Using a retroviral vector to express En1 ectopically, we show that En1 can induce Fgf8 expression in midbrain and posterior diencephalon. Results of the introduction of FGF8 protein into the anterior midbrain or posterior diencephalon are consistent with it being at least part of the isthmic activity which can repolarise the former tissue and respecify the latter to a midbrain fate. However, the ability of FGF8 to induce expression of genes which have earlier onsets of expression than Fgf8 itself, namely En1 and Pax2, strongly suggests that the normal function of FGF8 is in maintaining patterns of gene expression in posterior midbrain. Finally, we provide evidence that FGF8 also provides mitogenic stimulation during avian midbrain development.

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PubMed1999

The role of SF/HGF and c-Met in the development of skeletal muscle.

Hypaxial skeletal muscles develop from migratory and non-migratory precursor cells that are generated by the lateral lip of the dermomyotome. Previous work shows that the formation of migratory precursors requires the c-Met and SF/HGF genes. We show here that in mice lacking c-Met or SF/HGF, the initial development of the dermomyotome proceeds appropriately and growth and survival of cells in the dermomyotome are not affected. Migratory precursors are also correctly specified, as monitored by the expression of Lbx1. However, these cells remain aggregated and fail to take up long range migration. We conclude that parallel but independent cues converge on the migratory hypaxial precursors in the dermomyotomal lip after they are laid down: a signal given by SF/HGF that controls the emigration of the precursors, and an as yet unidentified signal that controls Lbx1. SF/HGF and c-Met act in a paracrine manner to control emigration, and migratory cells only dissociate from somites located close to SF/HGF-expressing cells. During long range migration, prolonged receptor-ligand-interaction appears to be required, as SF/HGF is expressed both along the routes and at the target sites of migratory myogenic progenitors. Mice that lack c-Met die during the second part of gestation due to a placental defect. Rescue of the placental defect by aggregation of tetraploid (wild type) and diploid (c-Met-/-) morulae allows development of c-Met mutant animals to term. They lack muscle groups that derive from migratory precursor cells, but display otherwise normal skeletal musculature.

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PubMed1999

The role of the notochord for epaxial myotome formation in the mouse.

The vertebrate somite is the source of all trunk skeletal muscles. Myogenesis in avian embryos is thought to depend on signals from notochord and neural tube for the epaxial muscles, and signals from lateral mesoderm and surface ectoderm for the hypaxial muscles. However, this hypothesis has to be tested because in mouse mutants lacking a notochord the presence of a fused myotome beneath the neural tube has been reported. We have compared the expression pattern of myogenic markers and markers for the hypaxial muscle precursors in the mutants Brachyury curtailed, truncate, Danforth's short tail and Pintail. In regions lacking notochord and sclerotome, we found small, ventrally located domains of Myf5 and MyoD expression, concomitant with ventrally expanded Pax3 signals and upregulated expression of the hypaxial marker Lbx1, suggesting that only the hypaxial program is active. We therefore hypothesise that in mammals, as in birds, the formation of the epaxial musculature depends on the presence of notochord derived signals.

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PubMed1998

Tlx-1 and Tlx-3 homeobox gene expression in cranial sensory ganglia and hindbrain of the chick embryo: markers of patterned connectivity.

Recent evidence suggests that in vertebrates the formation of distinct neuronal cell types is controlled by specific families of homeodomain transcription factors. Furthermore, the expression domains of a number of these genes correlates with functionally integrated neuronal populations. We have isolated two members of the divergent T-cell leukemia translocation (HOX11/Tlx) homeobox gene family from chick, Tlx-1 and Tlx-3, and show that they are expressed in differentiating neurons of both the peripheral and central nervous systems. In the peripheral nervous system, Tlx-1 and Tlx-3 are expressed in overlapping domains within the placodally derived components of a number of cranial sensory ganglia. Tlx-3, unlike Tlx-1, is also expressed in neural crest-derived dorsal root and sympathetic ganglia. In the CNS, both genes are expressed in longitudinal columns of neurons at specific dorsoventral levels of the hindbrain. Each column has distinct anterior and/or posterior limits that respect inter-rhombomeric boundaries. Tlx-3 is also expressed in D2 and D3 neurons of the spinal cord. Tlx-1 and Tlx-3 expression patterns within the peripheral and central nervous systems suggest that Tlx proteins may be involved not only in the differentiation and/or survival of specific neuronal populations but also in the establishment of neuronal circuitry. Furthermore, by analogy with the LIM genes, Tlx family members potentially define sensory columns early within the developing hindbrain in a combinatorial manner.

Amino Acid Sequence↗
PubMed1998

Differential progenitor dispersal and the spatial origin of early neurons can explain the predominance of single-phenotype clones in the chick hindbrain.

Clonal analysis of the chick embryo hindbrain has shown that during the first 48 hr of neurogenesis the large majority of neural progenitor cells generate clones of neurons of only a single major phenotype or of only closely related phenotypes. This is despite considerable spatial intermixing of diverse neuronal phenotypes at these stages of development and suggests that phenotype may be decided early in mitotic precursors and remembered through several subsequent rounds of division and dispersal (Lumsden et al. [1994] Development 120:1581-1589). Here we have used fate-mapping and clonal analysis to study neuroepithelial cell dispersal and mixing in the early hindbrain and discuss this data in relation to the generation of single phenotype neuronal clones. We find that dispersal is not uniform throughout the dorsoventral axis of the neural tube, but is highly dependent on position along that axis. Neuronal identity is related to the spatial origin and, hence, environment of the cell, and the spatial intermixing of diverse neuronal phenotypes at HH stage 20 is largely the result of circumferential neuronal migration as medially born branchial motor neurons migrate laterally while the more laterally born mlf neurons migrate medially. Constraints on the dispersal of clonally related progenitors, in particular those that lie adjacent to the floor plate, may serve to restrict the fate of these cells to the generation of only one major neuronal phenotype, i.e., motor neurons.

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PubMed1998

Dorsal spinal cord neuroepithelium generates astrocytes but not oligodendrocytes.

There is evidence that oligodendrocytes in the spinal cord are derived from a restricted part of the ventricular zone near the floor plate. An alternative view is that oligodendrocytes are generated from all parts of the ventricular zone. We reinvestigated glial origins by constructing chick-quail chimeras in which dorsal or ventral segments of the embryonic chick neural tube were replaced with equivalent segments of quail neural tube. Ventral grafts gave rise to both oligodendrocytes and astrocytes. In contrast, dorsal grafts produced astrocytes but not oligodendrocytes. In mixed cultures of ventral and dorsal cells, only ventral cells generated oligodendrocytes, whereas both ventral and dorsal cells generated astrocytes. Therefore, oligodendrocytes are derived specifically from ventral neuroepithelium, and astrocytes from both dorsal and ventral.

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PubMed1998

Specification of the hypaxial musculature.

During development of the amniote embryo, the dorsolateral territory of the somite is destined to give rise to the hypaxial skeletal musculature. To study the mechanisms that lead to the formation of this musculature, we cloned the chick Lbx1 gene that is specific to prospective hypaxial myoblasts at occipital, cervical and limb levels. Using this gene as a marker, we characterised the anatomical structures that produce the signals necessary for the specification of the hypaxial musculature by ablating them or transplanting them to ectopic locations in the chick embryo. In addition, we inserted BMP4 soaked beads medial to the somite. Our data suggest that lateralising signals from intermediate and lateral mesoderm have to synergise with dorsalising signals from the surface ectoderm to induce the formation of the hypaxial musculature. However, the lateralising function of the lateral mesoderm can only in part be mimicked by BMP4.

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PubMed1998

Hoxa1 and Hoxb1 synergize in patterning the hindbrain, cranial nerves and second pharyngeal arch.

The analysis of Hoxa1 and Hoxb1 null mutants suggested that these genes are involved in distinct aspects of hindbrain segmentation and specification. Here we investigate the possible functional synergy of the two genes. The generation of Hoxa1(3'RARE)/Hoxb1(3'RARE) compound mutants resulted in mild facial motor nerve defects reminiscent of those present in the Hoxb1 null mutants. Strong genetic interactions between Hoxa1 and Hoxb1 were uncovered by introducing the Hoxb1(3'RARE) and Hoxb1 null mutations into the Hoxa1 null genetic background. Hoxa1(null)/Hoxb1(3'RARE) and Hoxa1(null)/Hoxb1(null )double homozygous embryos showed additional patterning defects in the r4-r6 region but maintained a molecularly distinct r4-like territory. Neurofilament staining and retrograde labelling of motor neurons indicated that Hoxa1 and Hoxb1 synergise in patterning the VIIth through XIth cranial nerves. The second arch expression of neural crest cell markers was abolished or dramatically reduced, suggesting a defect in this cell population. Strikingly, the second arch of the double mutant embryos involuted by 10.5 dpc and this resulted in loss of all second arch-derived elements and complete disruption of external and middle ear development. Additional defects, most notably the lack of tympanic ring, were found in first arch-derived elements, suggesting that interactions between first and second arch take place during development. Taken together, our results unveil an extensive functional synergy between Hoxa1 and Hoxb1 that was not anticipated from the phenotypes of the simple null mutants.

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