Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurogenesis in Xenopus neural ectoderm involves multiple gene families, including basic helix-loop-helix transcription factors, which initiate and control primary neurogenesis. Equally important, though less well understood, are the downstream effectors of the activity of these transcription factors. We have investigated the role of a candidate downstream effector, Noelin-1, during Xenopus development. Noelin-1 is a secreted glycoprotein that likely forms large multiunit complexes. In avians, overexpression of Noelin-1 causes prolonged and excessive neural crest migration. Our studies in Xenopus reveal that this gene, while highly conserved in sequence, has a divergent function in primary neurogenesis. Xenopus Noelin-1 is expressed mainly by postmitotic neurogenic tissues in the developing central and peripheral nervous systems, first appearing after neural tube closure. Its expression is upregulated in ectopic locations upon overexpression of the neurogenic genes X-ngnr-1 and XNeuroD. Noelin-1 expression in animal caps induces expression of neural markers XBrn-3d and XNeuroD, and co-expression of secreted Noelin-1 with noggin amplifies noggin-induced expression of XBrn-3d and XNeuroD. Furthermore, in animal caps neuralized by expression of noggin, co-expression of Noelin-1 causes expression of neuronal differentiation markers several stages before neurogenesis normally occurs in this tissue. Finally, only secreted forms of the protein can activate sensory marker expression, while all forms of the protein can induce early neurogenesis. This suggests that the cellular localization of Noelin-1 may be important to its function. Thus, Noelin-1 represents a novel secreted factor involved in neurogenesis.
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PMID:The secreted glycoprotein Noelin-1 promotes neurogenesis in Xenopus. 1178 68

Id proteins bind basic helix-loop-helix transcription factors and function as dominant negative inhibitors of gene expression. Id1 and Id3 are required for the recruitment of bone marrow-derived endothelial cell precursors and tumors transplanted into Id-deficient mice demonstrate impaired angiogenesis. Mouse mammary tumor virus-neu mice were bred with Id1-/-Id3+/- mice to ascertain the role of Id1 and Id3 in mammary tumorigenesis in a more physiologically relevant model. In mammary tumors from these mice, Id1 and Id3 expression was restricted to the vascular endothelium. Id1 and Id3 deficiency did not prevent or delay tumor formation but did alter tumor phenotype. The tumors that developed in the Id-deficient mice were larger and cystic with a viable rim of tumor cells surrounding a nonviable core of cellular debris. The Hsp90 chaperone protein is required for cellular survival under condition of environmental stress and for the stability of the neu oncogene. 17-Allylamino-17-demethoxygeldanamycin, an Hsp90 inhibitor, was used to treat these mice. Whereas 17-allylamino-17-demethoxygeldanamycin only modestly delayed the growth of established mammary tumors in WT mice for Id, tumor suppression was dramatically more effective in an Id1- or Id3-deficient background. These data suggest that tumorigenesis can occur in a background of defective angiogenesis but that tumors developing in such an environment may be especially sensitive to inhibitors of neu and stress-activated survival pathways. Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer.
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PMID:Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors. 1452 2

Transcriptional cis-regulatory modules (CRMs), or enhancers, are responsible for directing gene expression in specific territories and cell types during development. In some instances, the same gene may be served by two or more enhancers with similar specificities. Here we show that the utilization of dual, or "shadow", enhancers is a common feature of genes that are active specifically in neural precursor (NP) cells in Drosophila. By genome-wide computational discovery of statistically significant clusters of binding motifs for both proneural activator (P) proteins and basic helix-loop-helix (bHLH) repressor (R) factors (a "P+R" regulatory code), we have identified NP-specific enhancer modules associated with multiple genes expressed in this cell type. These CRMs are distinct from those previously identified for the corresponding gene, establishing the existence of a dual-enhancer arrangement in which both modules reside close to the gene they serve. Using wild-type and mutant reporter gene constructs in vivo, we show that P sites in these modules mediate activation by proneural factors in "proneural cluster" territories, whereas R sites mediate repression by bHLH repressors, which serves to restrict expression specifically to NP cells. To our knowledge, our results identify the first direct targets of these bHLH repressors. Finally, using genomic rescue constructs for neuralized (neur), we demonstrate that each of the gene's two NP-specific enhancers is sufficient to rescue neur function in the lateral inhibition process by which adult sensory organ precursor (SOP) cells are specified, but that deletion of both enhancers results in failure of this event.
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PMID:Neural precursor-specific expression of multiple Drosophila genes is driven by dual enhancer modules with overlapping function. 2540 15

Developmental patterning involves the progressive subdivision of tissue into different cell types by invoking different genetic programs. In particular, cell-cell signaling is a universally deployed means of specifying distinct cell fates in adjacent cells. For this mechanism to be effective, it is essential that an asymmetry be established in the signaling and responding capacities of the participating cells. Here we focus on the regulatory mechanisms underlying the role of the neuralized gene and its protein product in establishing and maintaining asymmetry of signaling through the Notch pathway. The context is the classical process of "lateral inhibition" within Drosophila proneural clusters, which is responsible for distinguishing the sensory organ precursor (SOP) and non-SOP fates among adjacent cells. We find that neur is directly regulated in proneural clusters by both proneural transcriptional activators and Enhancer of split basic helix-loop-helix repressors (bHLH-Rs), via two separate cis-regulatory modules within the neur locus. We show that this bHLH-R regulation is required to prevent the early, pre-SOP expression of neur from being maintained in a subset of non-SOPs following SOP specification. Lastly, we demonstrate that Neur activity in the SOP is required to inhibit, in a cell non-autonomous manner, both neur expression and Neur function in non-SOPs, thus helping to secure the robust establishment of distinct cell identities within the developing proneural cluster.
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PMID:Lateral inhibition: Two modes of non-autonomous negative autoregulation by neuralized. 3002 87