Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development

Yiai Tong, Thomas J. Ha, Li Liu, Andrew Nishimoto, Anton Reiner, Dan Goldowitz

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Huntington's disease (HD), caused by an expanded triplet repeat in the huntingtin (Htt) gene, results in extensive neuropathology, but study of the Htt gene in CNS development through gene knockout is problematic as the knockout leads to embryonic lethality in mice. Here, we report that the knockdown of Htt expression in neuroepithelial cells of neocortex results in disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, however, Htt knockdown results in cell death but not perturbed migration. The cell death phenotype in cortex can be partially reversed with co-knockdown of Casp9, indicating that mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knockdown during early development is also an important variable. These results indicate a spatial and temporal requirement for Htt expression in neural development. Although it is uncertain whether the loss of wild-type huntingtin function contributes to pathogenesis in Huntington's disease, these results clearly contraindicate the use of nonspecific knockdown of Htt as a therapeutic measure in HD, particularly in utero.

Original languageEnglish (US)
Pages (from-to)14794-14799
Number of pages6
JournalJournal of Neuroscience
Volume31
Issue number41
DOIs
StatePublished - Oct 12 2011

Fingerprint

Huntington Disease
Cell Death
Brain
Neuroepithelial Cells
Trinucleotide Repeats
Gene Knockout Techniques
Neocortex
Cerebellum
Genes
Cell Movement
Mitochondria
Phenotype
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. / Tong, Yiai; Ha, Thomas J.; Liu, Li; Nishimoto, Andrew; Reiner, Anton; Goldowitz, Dan.

In: Journal of Neuroscience, Vol. 31, No. 41, 12.10.2011, p. 14794-14799.

Research output: Contribution to journalArticle

Tong, Yiai ; Ha, Thomas J. ; Liu, Li ; Nishimoto, Andrew ; Reiner, Anton ; Goldowitz, Dan. / Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 41. pp. 14794-14799.
@article{6d5fbde9b00e4ccdaca54e0f122ab28c,
title = "Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development",
abstract = "Huntington's disease (HD), caused by an expanded triplet repeat in the huntingtin (Htt) gene, results in extensive neuropathology, but study of the Htt gene in CNS development through gene knockout is problematic as the knockout leads to embryonic lethality in mice. Here, we report that the knockdown of Htt expression in neuroepithelial cells of neocortex results in disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, however, Htt knockdown results in cell death but not perturbed migration. The cell death phenotype in cortex can be partially reversed with co-knockdown of Casp9, indicating that mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knockdown during early development is also an important variable. These results indicate a spatial and temporal requirement for Htt expression in neural development. Although it is uncertain whether the loss of wild-type huntingtin function contributes to pathogenesis in Huntington's disease, these results clearly contraindicate the use of nonspecific knockdown of Htt as a therapeutic measure in HD, particularly in utero.",
author = "Yiai Tong and Ha, {Thomas J.} and Li Liu and Andrew Nishimoto and Anton Reiner and Dan Goldowitz",
year = "2011",
month = "10",
day = "12",
doi = "10.1523/JNEUROSCI.2774-11.2011",
language = "English (US)",
volume = "31",
pages = "14794--14799",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "41",

}

TY - JOUR

T1 - Spatial and temporal requirements for huntingtin (Htt) in neuronal migration and survival during brain development

AU - Tong, Yiai

AU - Ha, Thomas J.

AU - Liu, Li

AU - Nishimoto, Andrew

AU - Reiner, Anton

AU - Goldowitz, Dan

PY - 2011/10/12

Y1 - 2011/10/12

N2 - Huntington's disease (HD), caused by an expanded triplet repeat in the huntingtin (Htt) gene, results in extensive neuropathology, but study of the Htt gene in CNS development through gene knockout is problematic as the knockout leads to embryonic lethality in mice. Here, we report that the knockdown of Htt expression in neuroepithelial cells of neocortex results in disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, however, Htt knockdown results in cell death but not perturbed migration. The cell death phenotype in cortex can be partially reversed with co-knockdown of Casp9, indicating that mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knockdown during early development is also an important variable. These results indicate a spatial and temporal requirement for Htt expression in neural development. Although it is uncertain whether the loss of wild-type huntingtin function contributes to pathogenesis in Huntington's disease, these results clearly contraindicate the use of nonspecific knockdown of Htt as a therapeutic measure in HD, particularly in utero.

AB - Huntington's disease (HD), caused by an expanded triplet repeat in the huntingtin (Htt) gene, results in extensive neuropathology, but study of the Htt gene in CNS development through gene knockout is problematic as the knockout leads to embryonic lethality in mice. Here, we report that the knockdown of Htt expression in neuroepithelial cells of neocortex results in disturbed cell migration, reduced proliferation, and increased cell death that is relatively specific to early neural development. In the cerebellum, however, Htt knockdown results in cell death but not perturbed migration. The cell death phenotype in cortex can be partially reversed with co-knockdown of Casp9, indicating that mitochondria-mediated cell apoptotic processes are involved in the neuronal death. The timing of knockdown during early development is also an important variable. These results indicate a spatial and temporal requirement for Htt expression in neural development. Although it is uncertain whether the loss of wild-type huntingtin function contributes to pathogenesis in Huntington's disease, these results clearly contraindicate the use of nonspecific knockdown of Htt as a therapeutic measure in HD, particularly in utero.

UR - http://www.scopus.com/inward/record.url?scp=80054013637&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054013637&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2774-11.2011

DO - 10.1523/JNEUROSCI.2774-11.2011

M3 - Article

VL - 31

SP - 14794

EP - 14799

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 41

ER -