Heat shock and the role of the HSPs during neural plate induction in early mammalian CNS and brain development

Walsh, David A.; Li, Z.; Wu, Yi-Mi; Nagata, Kazuhiro

doi:10.1007/pl00000592

Cited by 79 publications

(50 citation statements)

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“…Age-dependent demyelination and astrogliosis in hsf-deficient mice Hsf1 is expressed in neurons, astrocytes, and oligodendrocytes (Walsh et al, 1997;Stacchiotti et al, 1999), whereas Hsf2 is expressed in neurons and glia and the developing cerebral cortex (Stacchiotti et al, 1999;G. Wang et al, 2003;Chang et al, 2006) and Hsf4 is expressed in CNS of developing embryos, certain neuronal cell population, but not in astrocytes ) (data not shown).…”

Section: Resultsmentioning

confidence: 92%

Demyelination, Astrogliosis, and Accumulation of Ubiquitinated Proteins, Hallmarks of CNS Disease inhsf1-Deficient Mice

Homma¹,

Jin²,

Wang³

et al. 2007

J. Neurosci.

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The heat shock transcription factors (Hsfs) are responsible for the heat shock response, an evolutionarily conserved process for clearance of damaged and aggregated proteins. In organisms such as Caenorhabditis elegans, which contain a single Hsf, reduction in the level of Hsf is associated with the appearance of age-related phenotypes and increased accumulation of protein aggregates. Mammalian cells express three hsfs (hsf1, hsf2, hsf4) and their role in CNS homeostasis remains unclear. In this study, we examined the effects of deletion of single or multiple hsf genes in the CNS using mutant mice. Our results show that hsf1 Ϫ/Ϫ mice display progressive myelin loss that accompanies severe astrogliosis and this is exacerbated in the absence of either the hsf2 or hsf4 gene. Magnetic resonance imaging and behavioral studies indicate reduction in the white matter tracts of the corpus callosum, and deficiencies in motor activity, respectively, in aged hsf1 Ϫ/Ϫ mice. Concomitantly, hsf1 Ϫ/Ϫ aged CNS exhibit increased activated microglia and apoptotic cells that are mainly positive for GFAP, an astrocyte-specific marker. Studies based on the expression of short-lived ubiquitinated green fluorescent protein (GFPu) in living hsf1Ϫ/Ϫ cells indicate that they exhibit reduced ability to degrade ubiquitinated proteins, accumulate short-lived GFPu, and accumulate aggregates of the Huntington's model of GFP containing trinucleotide repeats (Q103-GFP). Likewise, hsf1 Ϫ/Ϫ brain and astrocytes exhibit higher than wild-type levels of ubiquitinated proteins, increased levels of protein oxidation, and increased sensitivity to oxidative stress. These studies indicate a critical role for mammalian hsf genes, but specifically hsf1, in the quality control mechanisms and maintenance of CNS homeostasis during the organism's lifetime.

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Section: Resultsmentioning

confidence: 92%

Demyelination, Astrogliosis, and Accumulation of Ubiquitinated Proteins, Hallmarks of CNS Disease inhsf1-Deficient Mice

Homma¹,

Jin²,

Wang³

et al. 2007

J. Neurosci.

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“…Further, heat shock-induced phosphorylation of both p38 and HSP27 was reduced in MEKK4 K1361R cells, suggesting an important role for MEKK4 in the heat shock-induced stress response. We could not detect phospho-HSP27 in embryo cryosections, due to the insensitivity of the available antibodies but not due to lack of expression, as HSP27 message is constitutively expressed in the developing central nervous system (21,35). As an in vitro validation of MEKK4 regulation of HSP27, MEKK4 K1361R MEFs exposed to heat shock demonstrated a reduction in the stability of actin microfilaments.…”

Section: Discussionmentioning

confidence: 89%

Ablation of MEKK4 Kinase Activity Causes Neurulation and Skeletal Patterning Defects in the Mouse Embryo

Abell

Rivera-Pérez

Cuevas

et al. 2005

Molecular and Cellular Biology

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Skeletal disorders and neural tube closure defects represent clinically significant human malformations. The signaling networks regulating normal skeletal patterning and neurulation are largely unknown. Targeted mutation of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4 K1361R ). Embryos homozygous for this mutation die at birth as a result of skeletal malformations and neural tube defects. Hindbrains of exencephalic MEKK4 K1361R embryos show a striking increase in neuroepithelial cell apoptosis and a dramatic loss of phosphorylation of MKK3 and -6, mitogen-activated protein kinase kinases (MKKs) regulated by MEKK4 in the p38 pathway. Phosphorylation of MAPK-activated protein kinase 2, a p38 substrate, is also inhibited, demonstrating a loss of p38 activity in MEKK4 K1361R embryos. In contrast, the MEK1/2-extracellular signal-regulated kinase 1 (ERK1)/ERK2 and MKK4-Jun N-terminal protein kinase pathways were unaffected. The p38 pathway has been shown to regulate the phosphorylation and expression of the small heat shock protein HSP27. Compared to the wild type, MEKK4 K1361R fibroblasts showed significantly reduced phosphorylation of p38 and HSP27, with a corresponding heat shock-induced instability of the actin cytoskeleton. Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream of p38 control cellular homeostasis. The findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation.Mitogen-activated protein kinases (MAPKs) can be divided into five distinct groups that include extracellular signal-regulated kinase 1 (ERK1) and ERK2, c-Jun N-terminal kinase (JNK), p38, ERK3 and ERK4, and ERK5 (10, 34). Each MAPK is activated by MAPK kinases (MAP2Ks). ERK1 and ERK2 are phosphorylated by MEK1 and MEK2 and are primarily activated by growth-promoting stimuli. JNK is activated by its MAP2Ks, MAPK kinase 4 (MKK4) and MKK7, whereas p38 is primarily activated by MKK3 and MKK6 (MKK3/6) but can be phosphorylated by MKK4 under some circumstances (4). JNK and p38 are mainly activated by stress stimuli and cytokines but can also be stimulated by growth factors. MAP2Ks are in turn regulated by MAPK kinase kinases (MAP3Ks). MEK kinase 4 (MEKK4) is a MAP3K that regulates p38 and JNK through the phosphorylation of the MAP2Ks MKK3 and MKK6 and MKK4 and MKK7, respectively (11, 31). The physiological role of MEKK4 is poorly defined, and the pathways that promote MEKK4 signaling to MAPKs are largely unknown.Vertebrate development is orchestrated by cell-cell interactions and cytokine gradients that regulate intracellular signaling networks. We have discovered that MEKK4 expression is regulated during development and is a critical node for the control of neural tube closure and skeletal patterning in the developing mouse embryo. In this report, we investigated the function of MEKK4 in development by the targeted inhibition of MEKK4 kinase activity. The MEKK4 gene was altered by the targeted mutation of the active site lys...

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“…Moreover, it is a protective agent under stress conditions and is involved in protein renaturation and refolding (33). In the developing mammalian nervous system, HSP90 is highly expressed in the G 0 phase of cells during neuroectoderm differentiation, suggesting that it is required in order to maintain cells in this phase (34). Moreover, Loones et al (35) have reported the differential expression of HSP90 in various regions of the developing nervous system, suggesting involvement of this molecule in specific functions distinct from its chaperone activity.…”

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confidence: 99%

Involvement of Cell Surface HSP90 in Cell Migration Reveals a Novel Role in the Developing Nervous System

Sidera

Samiotaki

Yfanti

et al. 2004

Journal of Biological Chemistry

113

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Heat shock protein HSP90 plays important roles in cellular regulation, primarily as a chaperone for a number of key intracellular proteins. We report here that the two HSP90 isoforms, ␣ and ␤, also localize on the surface of cells in the nervous system and are involved in their migration. A 94-kDa surface antigen, the 4C5 antigen, which was previously shown to be involved in migration processes during development of the nervous system, is shown to be identical to HSP90␣ using mass spectrometry analysis. This identity is further confirmed by immunoprecipitation experiments and by induction of 4C5 antigen expression in heat shock-treated embryonic rat brain cultures. Moreover, immunocytochemistry on live cerebellar rat cells reveals cell surface localization of both HSP90␣ and -␤. Cell migration from cerebellar and sciatic nerve explants is inhibited by anti-HSP90␣ and anti-HSP90␤ antibodies, similarly to the inhibition observed with monoclonal antibody 4C5. Moreover, immunostaining with rhodamine-phalloidin of migrating Schwann cells cultured in the presence of antibodies against both ␣ and ␤ isoforms of HSP90 reveals that HSP90 activity is associated with actin cytoskeletal organization, necessary for lamellipodia formation.The development of the vertebrate nervous system depends on extensive cell migration, which allows different cell types to reach their final destination and establish the composite organization of the adult nervous system. Cell migration is a complex process, which requires the coordination of many molecular and cellular events such as cell-cell recognition, adhesion, transmembrane signaling, and cell motility (1-23). The mechanisms underlying these processes involve orchestrated interactions between a large number of molecules (10, 24). Emerging evidence suggests that many proteins in the nervous system have multiple distinct functions. Thus, molecules involved in migration processes have been shown to participate additionally in other developmental events. These include the cell adhesion molecules (CAMs), which regulate axonal growth and regeneration (25); integrins, which mediate cell proliferation and synaptic plasticity (26); and neuregulins that promote neuronal differentiation and regulate glial commitment, proliferation, survival, and differentiation (27). We report here that heat shock protein 90 (HSP90) 1 is also a multifunctional protein, processing a novel role in neuronal migration. HSP90 is a highly conserved molecule with a wide distribution in various species. It acts as capacitor of morphological evolution in Drosophila melanogaster (28 -30). It also functions as a chaperone in unstressed cells, specifically involved in the folding or conformational regulation of central signal transduction molecules, including steroid hormone receptors and proto-oncogene kinases (31, 32). Moreover, it is a protective agent under stress conditions and is involved in protein renaturation and refolding (33). In the developing mammalian nervous system, HSP90 is highly expressed in the G 0 phase ...

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Heat shock and the role of the HSPs during neural plate induction in early mammalian CNS and brain development

Cited by 79 publications

References 78 publications

Demyelination, Astrogliosis, and Accumulation of Ubiquitinated Proteins, Hallmarks of CNS Disease inhsf1-Deficient Mice

Demyelination, Astrogliosis, and Accumulation of Ubiquitinated Proteins, Hallmarks of CNS Disease inhsf1-Deficient Mice

Ablation of MEKK4 Kinase Activity Causes Neurulation and Skeletal Patterning Defects in the Mouse Embryo

Involvement of Cell Surface HSP90 in Cell Migration Reveals a Novel Role in the Developing Nervous System

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