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Hypomorphic mutation of the mouse Huntington's disease gene orthologue

Vidya Murthy1, Toma Tebaldi2, Toshimi Yoshida3

  • 1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States of America.

Plos Genetics
|March 22, 2019
PubMed

Insights

Huntingtin (HTT) is crucial for organ development. Severe mutations in the mouse Htt gene cause developmental defects and lethality, highlighting its essential role from early development through organogenesis.

Area of Science:

  • Genetics
  • Developmental Biology
  • Neuroscience

Background:

  • Inactivating mutations in the Huntington's disease gene (HTT) suggest essential roles in organ development.
  • Understanding HTT's developmental functions is critical for comprehending Huntington's disease pathogenesis.

Purpose of the Study:

  • To investigate the in vivo developmental phenotypes associated with varying severities of Htt gene mutations.
  • To identify molecular mechanisms underlying Htt's role in embryonic development.

Main Methods:

  • Generation of mice with hypomorphic and null alleles of the Htt gene (HdhneoQ20, HdhneoQ50, HdhneoQ111, Hdhex4/5).
  • Phenotypic analysis of mutant embryos, including assessment of lethality, morphology, and hematopoiesis.
  • Comparative molecular analysis of wild-type and Htt-null cells using retinoic acid differentiation.

Main Results:

  • The most severe hypomorphic Htt allele did not rescue null lethality at gastrulation.
  • Intermediate hypomorphic alleles caused perinatal lethality and fetal abnormalities (body size, skin, skeletal, ear, hematopoiesis).
  • Molecular analysis revealed gene network dysregulation involving polycomb repressive complexes and miRNAs in Htt-null cells.

Conclusions:

  • Htt is essential for embryonic development, required both before and after gastrulation.
  • Htt mutations lead to a spectrum of developmental defects, indicating dose-dependent requirement.
  • Polycomb repressive complexes and miRNAs are implicated as molecular mediators of Htt's developmental functions.

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