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The flathead mutation causes CNS-specific developmental abnormalities and apoptosis.

M R Roberts1, K Bittman, W W Li

  • 1Department of Physiology, University of Connecticut, Storrs, Connecticut 06269, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|March 8, 2000
PubMed
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A new rat mutation, flathead (fh), causes severe brain size reduction due to increased cell death during development. This genetic defect impacts late-born neurons, leading to neurological issues and premature death.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • A novel autosomal recessive mutation, flathead (fh), was identified in Wistar rats.
  • The fh mutation leads to a significant reduction in brain size (40% of normal at birth).
  • Affected rats exhibit neurological deficits including seizures, tremor, impaired coordination, and premature death.

Purpose of the Study:

  • To investigate the genetic and cellular mechanisms underlying the brain size reduction in flathead rats.
  • To identify the developmental stage and cell types affected by the fh mutation.

Main Methods:

  • Behavioral analysis of fh/fh rats.
  • Bromodeoxyuridine (BrdU) incorporation assays to assess cell proliferation.
  • In situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL) assays to detect apoptotic cell death.

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  • Histological examination of brain structures.

    • Main Results:

    • Cell proliferation rates in the fh/fh cortex were comparable to controls.
    • A significant increase in apoptotic cell death was observed in the fh/fh neocortex starting after embryonic day 16 (E16).
    • Late-developing brain structures, including the neocortex, hippocampus, cerebellum, and retina, were most severely affected, with selective depletion of later-generated neuronal populations.

    Conclusions:

    • The flathead gene is crucial for normal brain development, specifically for the generation and maturation of late-born neuronal populations.
    • Abnormally high apoptosis during a critical developmental window is the primary cause of reduced brain growth in fh/fh rats.
    • The fh mutation provides a valuable model for studying the genetic control of neurodevelopment and neuronal cell death.