The Homeodomain Factor Lbx1 Distinguishes Two Major Programs of Neuronal Differentiation in the Dorsal Spinal Cord

Müller, Thomas; Brohmann, Henning; Pierani, Alessandra; Heppenstall, Paul A.; Lewin, Gary R.; Jessell, Thomas M.; Birchmeier, Carmen

doi:10.1016/s0896-6273(02)00689-x

Cited by 350 publications

(465 citation statements)

References 41 publications

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“…Formally, the altered fate of a specific population of neurons could change the timing of myelination and delay or decrease oligodendrocyte maturation. However, the number of neurons in the DI1 and DI2 population are very small relative to the total and the dorsal spinal cord neuronal subtypes develop within the same time period (Muller et al, 2002), suggesting that the effect would not account for the significant decrease we find. The generation of oligodendrocyte-specific BMP receptor knockouts will begin to address these questions.…”

Section: Discussionmentioning

confidence: 64%

BMP signaling mutant mice exhibit glial cell maturation defects

See

Mamontov

Ahn

et al. 2007

Molecular and Cellular Neuroscience

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Bone morphogenetic proteins have been implicated in the development of oligodendrocytes and astrocytes, however, a role for endogenous BMP signaling in glial development has not been demonstrated in a genetic model. Using mice in which signaling via type I BMP receptors Bmpr1a and Bmpr1b have been inactivated in the neural tube, we demonstrate that BMP signaling contributes to the maturation of glial cells in vivo. At P0, mutant mice exhibited a 25-40% decrease in GFAP+ or S100β+ astrocytes in the cervical spinal cord. The number of oligodendrocyte precursors and the timing of their emergence was unchanged in the mutant mice compared to the normals, however myelin protein expression and mature oligodendrocyte numbers were significantly reduced. These data indicate that BMP signaling promotes the generation of astrocytes and mature, myelinating oligodendrocytes in vivo but does not affect oligodendrocyte precursor development, thus suggesting tight regulation of BMP signaling to ensure proper gliogenesis.

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Section: Discussionmentioning

confidence: 64%

BMP signaling mutant mice exhibit glial cell maturation defects

See

Mamontov

Ahn

et al. 2007

Molecular and Cellular Neuroscience

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“…Thus, patterning of the ventral neural tube seems to be achieved by the derepression strategy (5,24). In addition, some postmitotically expressed homeodomain transcription factors have a putative EH1 motif (24) and have been shown to repress the expression of transcription factors, which are normally expressed in other types of neurons, in specifying neuronal identity (25)(26)(27)(28)(29)(30). Thus, the derepression mechanism might also be involved in postmitotic specification events.…”

Section: The Nucleotide Sequence(s) Reported In This Paper Has Been Smentioning

confidence: 99%

Corl1, a Novel Neuronal Lineage-specific Transcriptional Corepressor for the Homeodomain Transcription Factor Lbx1

Mizuhara

Nakatani

Minaki

et al. 2005

Journal of Biological Chemistry

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During development, neuronal identity is determined by a combination of numerous transcription factors. However, the mechanisms of synergistic action of these factors in transcriptional regulation and subsequent cell fate specification are largely unknown. In this study, we identified a novel gene, Corl1, encoding a nuclear protein with homology to the Ski oncoprotein. Corl1 was highly selectively expressed in the central nervous system (CNS). In the embryonic CNS, Corl1 was expressed in a certain subset of postmitotic neurons generated posterior to the midbrain-hindbrain border. In the developing spinal cord, Corl1 was selectively expressed in the dorsal horn interneurons where a homeodomain transcription factor, Lbx1, is required for proper specification. Corl1 was localized in a nuclear dot-like structure and interacted with general transcriptional corepressors. In addition, Corl1 showed transcriptional repression activity in the GAL4-fusion system, indicating its involvement in the regulation of transcriptional repression. Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord. Corl1 corepressor activity did not depend on Gro/TLE activity, and Gro/TLE also functioned as a corepressor for Lbx1. Thus, Lbx1 can select two independent partners, Corl1 and Gro/TLE, as corepressors. Identification of a novel transcriptional corepressor with neuronal subtype-restricted expression might provide insights into the mechanisms of cell fate determination in neurons.Neuronal patterning is regulated by extrinsic inductive signals and downstream intrinsic signals mediated by transcription factors (1-4). In early development, neural progenitor cells are specified by secreted molecules such as sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), 1 Wnts and fibroblast growth factors, which regulate the expression pattern of downstream transcription factors including bHLH and homeodomain factors. These signals regulate sets of transcription factors at different concentration thresholds. Thus, the neural tube is regionalized into distinct progenitor domains expressing different sets of transcription factors along the anteroposterior and dorsoventral axes depending on distance from the organizing centers expressing secreted factors. As development proceeds, different classes of postmitotic neurons emerge from the individual progenitor domains during neurogenesis.Accumulating evidence has elucidated the mechanism of development in several central nervous system (CNS) regions. For example, in the ventral spinal cord, the gradient of Shh, which is secreted from the organizer regions, notochord and floor plate, is established in the ventral half of the neural tube during early development (2, 5). Graded Shh repressed expression of the class I homeodomain transcription factors, and instead induced the class II transcription factors (6). Crossinhibitory interactions between co...

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“…Helt expression was compared with the expression of ␤III-tubulin and Lim1 as a postmitotic neuronal marker (41,42). As shown in Fig.…”

Section: Fig 2 Helt Homodimerizes and Heterodimerizes With Other Bmentioning

confidence: 99%

Helt, a Novel Basic-Helix-Loop-Helix Transcriptional Repressor Expressed in the Developing Central Nervous System

Nakatani

Mizuhara

Minaki

et al. 2004

Journal of Biological Chemistry

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Neuronal differentiation is regulated by many basichelix-loop-helix (bHLH) family transcriptional activators and repressors, and the balance of activity between these factors is important for the differentiation process. Here, we report the identification of a novel transcriptional repressor, designated Helt. Helt encoded a Hey-related bHLH protein containing the bHLH and Orange domains. Helt could homodimerize, and heterodimerize with Hes5 or Hey2. Both the bHLH and Orange domains were involved in the homodimerization. In contrast, only the bHLH domain was required for the heterodimerization with Hey2, whereas only the Orange domain mediated the interaction between Helt and Hes5. Thus, Helt has two dimerization domains, and these domains independently select a partner. Identification of preferred recognition sequences by CASTing experiments revealed that Helt bound to the E box, which was distinct from the Hes1 optimal sequence around the E box core. Not only the core sequence but also sequences flanking the E box were essential for the recognition by Helt and Hes1. Furthermore, Helt repressed transcription from an artificial promoter through binding to the optimal E box elements, as well as transcription from its own promoter. Using in situ hybridization and immunohistochemistry, Helt expression in embryos was investigated. Helt was mainly expressed in undifferentiated neural progenitors in some of the developing brain regions, including the mesencephalon and diencephalon, at the neurogenesis stage. These results suggest that Helt acts as a transcriptional repressor to regulate neuronal differentiation and/or identity.

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The Homeodomain Factor Lbx1 Distinguishes Two Major Programs of Neuronal Differentiation in the Dorsal Spinal Cord

Cited by 350 publications

References 41 publications

BMP signaling mutant mice exhibit glial cell maturation defects

BMP signaling mutant mice exhibit glial cell maturation defects

Corl1, a Novel Neuronal Lineage-specific Transcriptional Corepressor for the Homeodomain Transcription Factor Lbx1

Helt, a Novel Basic-Helix-Loop-Helix Transcriptional Repressor Expressed in the Developing Central Nervous System

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