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

Neurobiol Dis. 2016 Dec;96:144-155. doi: 10.1016/j.nbd.2016.09.006. Epub 2016 Sep 10.


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.

Keywords: Degeneration; Development; Gliogenesis; Huntingtin; Huntington's disease; Loss-of-function; Maturation; Myelin; Neurogenesis; Pathogenesis.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cell Differentiation / genetics
  • Developmental Disabilities / complications
  • Developmental Disabilities / genetics*
  • Disease Models, Animal
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental / genetics
  • Huntingtin Protein / deficiency*
  • Huntingtin Protein / genetics
  • Huntington Disease / complications*
  • Huntington Disease / genetics*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / complications
  • Neurodegenerative Diseases / etiology*
  • Psychomotor Disorders / etiology
  • Psychomotor Disorders / genetics
  • RNA, Messenger / metabolism
  • White Matter / pathology


  • Huntingtin Protein
  • Nerve Tissue Proteins
  • RNA, Messenger