Huntingtin interacting protein 1 can regulate neurogenesis in <i>Drosophila</i>

Moores, Justin N.; Roy, Sophie; Nicholson, Donald W.; Staveley, Brian E.

doi:10.1111/j.1460-9568.2008.06359.x

Cited by 7 publications

(6 citation statements)

References 50 publications

(155 reference statements)

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“…Even though Htt has not been found to directly interact with Notch, Hes1 or STAT3, our current findings do not rule out novel and indirect functional associations between these regulatory proteins. Indeed, recently reports have shown that: 1) Huntingtin interacting protein-1 (HIP1) can regulate Deltex-dependent Notch signaling for mediating neurogenesis in Drosophila [41] and 2) Hes1 is able to bind to STAT3 and to facilitate its expression and activation [29]. …”

Section: Discussionmentioning

confidence: 99%

Functions of Huntingtin in Germ Layer Specification and Organogenesis

et al. 2013

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Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC) expansion, differentiation and induction experiments using huntingtin knock-out (KO) and mutant huntingtin knock-in (Q111) mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities.

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Section: Discussionmentioning

confidence: 99%

Functions of Huntingtin in Germ Layer Specification and Organogenesis

et al. 2013

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“…Thus, one can associate the altered gene expression of γ-secretase components with abnormal proteolytic activity in HD (Tarlac and Storey, 2003 ). It was suggested that HTT-interacting protein HIP1 (huntingtin-interacting protein 1) may provide a functional link between non-canonical Notch signaling-mediated neurogenesis through a deltex -dependent pathway (Moores et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of genes encoding the calcium signalosome in cellular and transgenic models of Huntington's disease

Czeredys

Gruszczynska-Biegala

Schacht

et al. 2013

Front. Mol. Neurosci.

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Huntington's disease (HD) is a hereditary neurodegenerative disease caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein and characterized by dysregulated calcium homeostasis. We investigated whether these disturbances are correlated with changes in the mRNA level of the genes that encode proteins involved in calcium homeostasis and signaling (i.e., the calciosome). Using custom-made TaqMan low-density arrays containing probes for 96 genes, we quantified mRNA in the striatum in YAC128 mice, a model of HD, and wildtype mice. HTT mutation caused the increased expression of some components of the calcium signalosome, including calretinin, presenilin 2, and calmyrin 1, and the increased expression of genes indirectly involved in calcium homeostasis, such as huntingtin-associated protein 1 and calcyclin-binding protein. To verify these findings in a different model, we used PC12 cells with an inducible expression of mutated full-length HTT. Using single-cell imaging with Fura-2AM, we found that store-operated Ca2+ entry but not endoplasmic reticulum (ER) store content was changed as a result of the expression of mutant HTT. Statistically significant downregulation of the Orai calcium channel subunit 2, calmodulin, and septin 4 was detected in cells that expressed mutated HTT. Our data indicate that the dysregulation of calcium homeostasis correlates with changes in the gene expression of members of the calciosome. These changes, however, differed in the two models of HD used in this study. Our results indicate that each HD model exhibits distinct features that may only partially resemble the human disease.

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“…As appropriate Notch expression levels are important to direct ESC differentiation to neural lineages [41], the apparent normal levels of expression of Notch and Hes5 in KO FGF2-responsive dNSs suggest that Htt may not play a role in the regulation of Notch signaling in dNSCs, and that alterations in neuronal and glial lineage elaboration may be due, in part, to additional non-redundant developmental signaling pathways. Thus far, Htt has not been shown to have any direct interaction with components of the Notch signaling cascade, with the exception of a single study reporting an indirect functional association between Huntingtin interacting protein 1 (HIP-1) and deltex-dependent Notch signaling in Drosophila that plays a role in neurogenesis [42]. Additional studies are required to elucidate the mechanisms underlying this regulatory function.…”

Section: Discussionmentioning

confidence: 99%

Selective Roles of Normal and Mutant Huntingtin in Neural Induction and Early Neurogenesis

et al. 2013

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Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal polyglutamine expansion in the amino-terminal end of the huntingtin protein (Htt) and characterized by progressive striatal and cortical pathology. Previous reports have shown that Htt is essential for embryogenesis, and a recent study by our group revealed that the pathogenic form of Htt (mHtt) causes impairments in multiple stages of striatal development. In this study, we have examined whether HD-associated striatal developmental deficits are reflective of earlier maturational alterations occurring at the time of neurulation by assessing differential roles of Htt and mHtt during neural induction and early neurogenesis using an in vitro mouse embryonic stem cell (ESC) clonal assay system. We demonstrated that the loss of Htt in ESCs (KO ESCs) severely disrupts the specification of primitive and definitive neural stem cells (pNSCs, dNSCs, respectively) during the process of neural induction. In addition, clonally derived KO pNSCs and dNSCs displayed impaired proliferative potential, enhanced cell death and altered multi-lineage potential. Conversely, as observed in HD knock-in ESCs (Q111 ESCs), mHtt enhanced the number and size of pNSC clones, which exhibited enhanced proliferative potential and precocious neuronal differentiation. The transition from Q111 pNSCs to fibroblast growth factor 2 (FGF2)-responsive dNSCs was marked by potentiation in the number of dNSCs and altered proliferative potential. The multi-lineage potential of Q111 dNSCs was also enhanced with precocious neurogenesis and oligodendrocyte progenitor elaboration. The generation of Q111 epidermal growth factor (EGF)-responsive dNSCs was also compromised, whereas their multi-lineage potential was unaltered. These abnormalities in neural induction were associated with differential alterations in the expression profiles of Notch, Hes1 and Hes5. These cumulative observations indicate that Htt is required for multiple stages of neural induction, whereas mHtt enhances this process and promotes precocious neurogenesis and oligodendrocyte progenitor cell elaboration.

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Huntingtin interacting protein 1 can regulate neurogenesis in Drosophila

Cited by 7 publications

References 50 publications

Functions of Huntingtin in Germ Layer Specification and Organogenesis

Functions of Huntingtin in Germ Layer Specification and Organogenesis

Expression of genes encoding the calcium signalosome in cellular and transgenic models of Huntington's disease

Selective Roles of Normal and Mutant Huntingtin in Neural Induction and Early Neurogenesis

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