Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

Eduardo E. Arteaga-Bracho, Maria Gulinello, Michael L. Winchester, Nandini Pichamoorthy, Jenna R. Petronglo, Alicia D. Zambrano, Julio Inocencio, Chirstopher D. De Jesus, Joseph O. Louie, Solen Gokhan, Mark F. Mehler, Aldrin E. Molero

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington's disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdhd•hyp). We demonstrated that Hdhd•hyp mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdhd•hyp embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.

Original languageEnglish (US)
Pages (from-to)144-155
Number of pages12
JournalNeurobiology of Disease
StatePublished - Dec 1 2016


  • Degeneration
  • Development
  • Gliogenesis
  • Huntingtin
  • Huntington's disease
  • Loss-of-function
  • Maturation
  • Myelin
  • Neurogenesis
  • Pathogenesis

ASJC Scopus subject areas

  • Neurology


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