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T M Jessell

Publications and source records attributed to T M Jessell.

At least 19 recordsLinked to original sources
PubMed2001

Assigning the positional identity of spinal motor neurons: rostrocaudal patterning of Hox-c expression by FGFs, Gdf11, and retinoids.

Subclasses of motor neurons are generated at different positions along the rostrocaudal axis of the spinal cord. One feature of the rostrocaudal organization of spinal motor neurons is a position-dependent expression of Hox genes, but little is known about how this aspect of motor neuron subtype identity is assigned. We have used the expression profile of Hox-c proteins to define the source and identity of patterning signals that impose motor neuron positional identity along the rostrocaudal axis of the spinal cord. We provide evidence that the convergent activities of FGFs, Gdf11, and retinoid signals originating from Hensen's node and paraxial mesoderm establish and refine the Hox-c positional identity of motor neurons in the developing spinal cord.

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PubMed2001

Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2.

Within the developing vertebrate nervous system, the mechanisms that coordinate neuronal subtype identity with generic features of neuronal differentiation are poorly defined. We show here that a bHLH protein, Olig2, is expressed selectively by motor neuron progenitors and has a key role in specifying the subtype identity and pan-neuronal properties of developing motor neurons. The role of Olig2 in the specification of motor neuron subtype identity depends on regulatory interactions with progenitor homeodomain proteins, whereas its role in promoting pan-neuronal properties is associated with expression of another bHLH protein, Ngn2. Both aspects of Olig2 function appear to depend on its activity as a transcriptional repressor. Together, these studies show that Olig2 has a critical role in integrating diverse features of motor neuron differentiation in the developing spinal cord.

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PubMed2001

Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification.

Specification of neuronal fate in the vertebrate central nervous system depends on the profile of transcription factor expression by neural progenitor cells, but the precise roles of such factors in neurogenesis remain poorly characterized. Two closely related transcriptional repressors, Nkx6.2 and Nkx6.1, are expressed by progenitors in overlapping domains of the ventral spinal cord. We provide genetic evidence that differences in the level of repressor activity of these homeodomain proteins underlies the diversification of interneuron subtypes, and provides a fail-safe mechanism during motor neuron generation. A reduction in Nkx6 activity further permits V0 neurons to be generated from progenitors that lack homeodomain proteins normally required for their generation, providing direct evidence for a model in which progenitor homeodomain proteins direct specific cell fates by actively suppressing the expression of transcription factors that direct alternative fates.

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PubMed2001

The status of Wnt signalling regulates neural and epidermal fates in the chick embryo.

The acquisition of neural fate by embryonic ectodermal cells is a fundamental step in the formation of the vertebrate nervous system. Neural induction seems to involve signalling by fibroblast growth factors (FGFs) and attenuation of the activity of bone morphogenetic protein (BMP). But FGFs, either alone or in combination with BMP antagonists, are not sufficient to induce neural fate in prospective epidermal ectoderm of amniote embryos. These findings suggest that additional signals are involved in the specification of neural fate. Here we show that the state of Wnt signalling is a critical determinant of neural and epidermal fates in the chick embryo. Continual Wnt signalling blocks the response of epiblast cells to FGF signals, permitting the expression and signalling of BMP to direct an epidermal fate. Conversely, a lack of exposure of epiblast cells to Wnt signals permits FGFs to induce a neural fate.

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PubMed2001

Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.

BACKGROUND: Several Cre reporter strains of mice have been described, in which a lacZ gene is turned on in cells expressing Cre recombinase, as well as their daughter cells, following Cre-mediated excision of a loxP-flanked transcriptional "stop" sequence. These mice are useful for cell lineage tracing experiments as well as for monitoring the expression of Cre transgenes. The green fluorescent protein (GFP) and variants such as EYFP and ECFP offer an advantage over lacZ as a reporter, in that they can be easily visualized without recourse to the vital substrates required to visualize beta-gal in living tissue. RESULTS: In view of the general utility of targeting the ubiquitously expressed ROSA26 locus, we constructed a generic ROSA26 targeting vector. We then generated two reporter lines of mice by inserting EYFP or ECFP cDNAs into the ROSA26 locus, preceded by a loxP-flanked stop sequence. These strains were tested by crossing them with transgenic strains expressing Cre in a ubiquitous (beta-actin-Cre) or a cell-specific (Isl1-Cre and En1-Cre) pattern. The resulting EYFP or ECFP expression patterns indicated that the reporter strains function as faithful monitors of Cre activity. CONCLUSIONS: In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs. The non-overlapping emission spectra of EYFP and ECFP make them ideal for double labeling studies in living tissues.

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PubMed2001

Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube.

The pattern of neuronal specification in the ventral neural tube is controlled by homeodomain transcription factors expressed by neural progenitor cells, but no general logic has emerged to explain how these proteins determine neuronal fate. We show that most of these homeodomain proteins possess a conserved eh1 motif that mediates the recruitment of Gro/TLE corepressors. The eh1 motif underlies the function of these proteins as repressors during neural patterning in vivo. Inhibition of Gro/TLE-mediated repression in vivo results in a deregulation of cell pattern in the neural tube. These results imply that the pattern of neurogenesis in the neural tube is achieved through the spatially controlled repression of transcriptional repressors-a derepression strategy of neuronal fate specification.

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PubMed2001

Control of interneuron fate in the developing spinal cord by the progenitor homeodomain protein Dbx1.

Spinal interneurons help to coordinate motor behavior. During spinal cord development, distinct classes of interneurons are generated from progenitor cells located at different positions within the ventral neural tube. V0 and V1 interneurons derive from adjacent progenitor domains that are distinguished by expression of the homeodomain proteins Dbx1 and Dbx2. The spatially restricted expression of Dbx1 has a critical role in establishing the distinction in V0 and V1 neuronal fate. In Dbx1 mutant mice, neural progenitors fail to generate V0 neurons and instead give rise to interneurons that express many characteristics of V1 neurons-their transcription factor profile, neurotransmitter phenotype, migratory pattern, and aspects of their axonal trajectory. Thus, a single progenitor homeodomain transcription factor coordinates many of the differentiated properties of one class of interneurons generated in the ventral spinal cord.

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PubMed2001

Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation.

The patterning of skeletal muscle is thought to depend upon signals provided by motor neurons. We show that AChR gene expression and AChR clusters are concentrated in the central region of embryonic skeletal muscle in the absence of innervation. Neurally derived Agrin is dispensable for this early phase of AChR expression, but MuSK, a receptor tyrosine kinase activated by Agrin, is required to establish this AChR prepattern. The zone of AChR expression in muscle lacking motor axons is wider than normal, indicating that neural signals refine this muscle-autonomous prepattern. Neuronal Neuregulin-1, however, is not involved in this refinement process, nor indeed in synapse-specific AChR gene expression. Our results demonstrate that AChR expression is patterned in the absence of innervation, raising the possibility that similarly prepatterned muscle-derived cues restrict axon growth and initiate synapse formation.

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PubMed2001

A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube.

Cell pattern in the ventral neural tube is organized by Sonic hedgehog (Shh) secreted by floor plate cells. To assay the range of direct Shh action, we developed a general method for blocking transduction of Hedgehog (Hh) signals through ectopic expression of a deleted form of the Hh receptor Patched (Ptc), termed Ptc(Deltaloop2). We validated this method in Drosophila and used mouse Ptc1(Deltaloop2) (mPtc1(Deltaloop2)) to block Shh transduction in the chick neural tube. mPtc1(Deltaloop2) expression caused cell-autonomous ventral-to-dorsal switches in progenitor identity and neuronal fate throughout the ventral neural tube, supporting a gradient mechanism whereby Shh acts directly and at long range. mPtc1(Deltaloop2) expression also caused the abnormal spread of Shh to more dorsal cells, indicating that Shh in the neural tube, like Hh in Drosophila, induces a feedback mechanism that limits its range of action.

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PubMed2001

Progress in the neural sciences in the the century after Cajal (and the mysteries that remain).

One hundred years after Santiago Ramon y Cajal provided critical evidence for the "neuron doctrine," his cellular view of the brain remains the basis of modern neural science. This article begins with a review of how the early work of Ramon y Cajal, Charles Sherrington, and John Eccles and their contemporaries laid the groundwork for our current understanding of he information processing of neural systems and for understanding the task faced by studies of how the brain develops. The visual system is examined in some detail as a model for experimental investigation into the structure, operational mechanisms, and functions of large neural systems. Discussion of the phenomena of visual awareness and consciousness, links between the visual system and other brain systems, and disorders that disrupt voluntary control of cognition and emotion lead to a broader consideration of the problem of consciousness.

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PubMed2000

Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates.

There is growing evidence that sonic hedgehog (Shh) signaling regulates ventral neuronal fate in the vertebrate central nervous system through Nkx-class homeodomain proteins. We have examined the patterns of neurogenesis in mice carrying a targeted mutation in Nkx6.1. These mutants show a dorsal-to-ventral switch in the identity of progenitors and in the fate of postmitotic neurons. At many axial levels there is a complete block in the generation of V2 interneurons and motor neurons and a compensatory ventral expansion in the domain of generation of V1 neurons, demonstrating the essential functions of Nkx6.1 in regional patterning and neuronal fate determination.

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PubMed2000

Coordinate roles for LIM homeobox genes in directing the dorsoventral trajectory of motor axons in the vertebrate limb.

Motor neurons extend axons along specific trajectories, but the molecules that control their pathfinding remain poorly defined. We show that two LIM homeodomain transcription factors, Lim1 and Lmx1b, control the initial trajectory of motor axons in the developing mammalian limb. The expression of Lim1 by a lateral set of lateral motor column (LMC) neurons ensures that their axons select a dorsal trajectory in the limb. In a complementary manner, the expression of Lmx1b by dorsal limb mesenchymal cells controls the dorsal and ventral axonal trajectories of medial and lateral LMC neurons. In the absence of these two proteins, motor axons appear to select dorsal and ventral trajectories at random. Thus, LIM homeodomain proteins act within motor neurons and cells that guide motor axons to establish the fidelity of a binary choice in axonal trajectory.

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PubMed2000

Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling.

Topographic maps are a fundamental feature of sensory representations in nervous systems. The formation of one such map, defined by the connection of ganglion cells in the retina to their targets in the superior colliculus of the midbrain, is thought to depend upon an interaction between complementary gradients of retinal EphA receptors and collicular ephrin-A ligands. We have tested this hypothesis by using gene targeting to elevate EphA receptor expression in a subset of mouse ganglion cells, thereby producing two intermingled ganglion cell populations that express distinct EphA receptor gradients. We find that these two populations form separate maps in the colliculus, which can be predicted as a function of the net EphA receptor level that a given ganglion cell expresses relative to its neighbors.

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PubMed2000

Lim1 activity is required for intermediate mesoderm differentiation in the mouse embryo.

During gastrulation and early organogenesis, Lim1 is expressed in the visceral endoderm, the anterior mesendoderm, and the lateral mesoderm that comprises the lateral plate and intermediate mesoderm. A previous study has reported that kidneys and gonads are missing in the Lim1 null mutants (W. Shawlot and R. R. Behringer, 1995, Nature 374, 425-430). Results of the present study show that in the early organogenesis stage mutant embryo, the intermediate mesoderm that contains the urogenital precursor tissues is disorganized and displays diminished expression of PAX2 and the Hoxb6-lacZ transgene. When posterior epiblast cells of the Lim1 null mutant embryo were transplanted to the primitive streak of wild-type host embryos, they were able to colonize the lateral plate and intermediate mesoderm of the host, suggesting that Lim1 activity is not essential for the allocation of epiblast cells to these mesodermal lineages. However, most of the mutant cells that colonized the lateral and intermediate mesoderm of the host embryo did not express the Hoxb6-lacZ transgene, except for some cells that were derived from the distal part of the posterior epiblast. Lim1 activity may therefore be required for the full expression of this transgene that normally marks the differentiation of the lateral plate and intermediate mesoderm.

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PubMed2000

ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons.

The connections formed between sensory and motor neurons (MNs) play a critical role in the control of motor behavior. During development, the axons of proprioceptive sensory neurons project into the spinal cord and form both direct and indirect connections with MNs. Two ETS transcription factors, ER81 and PEA3, are expressed by developing proprioceptive neurons and MNs, raising the possibility that these genes are involved in the formation of sensory-motor connections. Er81 mutant mice exhibit a severe motor discoordination, yet the specification of MNs and induction of muscle spindles occurs normally. The motor defect in Er81 mutants results from a failure of group Ia proprioceptive afferents to form a discrete termination zone in the ventral spinal cord. As a consequence there is a dramatic reduction in the formation of direct connections between proprioceptive afferents and MNs. ER81 therefore controls a late step in the establishment of functional sensory-motor circuitry in the developing spinal cord.

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PubMed2000

A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube.

Distinct classes of neurons are generated at defined positions in the ventral neural tube in response to a gradient of Sonic Hedgehog (Shh) activity. A set of homeodomain transcription factors expressed by neural progenitors act as intermediaries in Shh-dependent neural patterning. These homeodomain factors fall into two classes: class I proteins are repressed by Shh and class II proteins require Shh signaling for their expression. The profile of class I and class II protein expression defines five progenitor domains, each of which generates a distinct class of postmitotic neurons. Cross-repressive interactions between class I and class II proteins appear to refine and maintain these progenitor domains. The combinatorial expression of three of these proteins--Nkx6.1, Nkx2.2, and Irx3--specifies the identity of three classes of neurons generated in the ventral third of the neural tube.

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PubMed2000

An early requirement for FGF signalling in the acquisition of neural cell fate in the chick embryo.

BACKGROUND: In Xenopus embryos, fibroblast growth factors (FGFs) and secreted inhibitors of bone morphogenetic protein (BMP)-mediated signalling have been implicated in neural induction. The precise roles, if any, that these factors play in neural induction in amniotes remains to be established. RESULTS: To monitor the initial steps of neural induction in the chick embryo, we developed an in vitro assay of neural differentiation in epiblast cells. Using this assay, we found evidence that neural cell fate is specified in utero, before the generation of the primitive streak or Hensen's node. Early epiblast cells expressed both Bmp4 and Bmp7, but the expression of both genes was downregulated as cells acquired neural fate. During prestreak and gastrula stages, exposure of epiblast cells to BMP4 activity in vitro was sufficient to block the acquisition of neural fate and to promote the generation of epidermal cells. Fgf3 was also found to be expressed in the early epiblast, and ongoing FGF signalling in epiblast cells was required for acquisition of neural fate and for the suppression of Bmp4 and Bmp7 expression. CONCLUSIONS: The onset of neural differentiation in the chick embryo occurs in utero, before the generation of Hensen's node. Fgf3, Bmp4 and Bmp7 are each expressed in prospective neural cells, and FGF signalling appears to be required for the repression of Bmp expression and for the acquisition of neural fate. Subsequent exposure of epiblast cells to BMPs, however, can prevent the generation of neural tissue and induce cells of epidermal character.

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