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The Journal of Neuroscience, March 15, 2000, 20(6):2295-2306

The Flathead Mutation Causes CNS-Specific Developmental Abnormalities and Apoptosis

Melanie R. Roberts¹, Kevin Bittman¹, Wei-Wei Li¹, Richard French², Bartley Mitchell³, Joseph J. LoTurco¹, and Santosh R. D'Mello³

Departments of ¹ Physiology and Neurobiology and ² Pathobiology, University of Connecticut, Storrs, Connecticut 06269, and ³ Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75083

We describe a new mutation, flathead (fh), that arose spontaneously in an inbred colony of Wistar rats. The mutation is autosomal recessive, and the behavioral phenotype of fh/fh rats includes spontaneous seizures, tremor, impaired coordination, and premature death. A striking feature of the fh mutation is a dramatic reduction in brain size (40% of normal at birth). In contrast, no abnormalities are evident in the peripheral nervous system or in other tissues outside of the CNS. Although bromodeoxyuridine incorporation assays indicate that the rate of cell proliferation in the fh/fh cortex is similar to that of unaffected animals, in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling assays reveal a dramatic increase in apoptotic cell death beginning after embryonic day 16 (E16). At E18 there is a 20-fold increase in cell death in the ventricular zone of fh/fh neocortex, and at postnatal day 1 (P1), the number of apoptotic cells is still two times that of normal. However, by P8 the extent of cell death in fh/fh is comparable to that of unaffected littermates, indicating that the reduction in brain growth is caused by abnormally high apoptosis during a discrete developmental period. Late-developing structures such as the cerebellum, neocortex, hippocampus, and retina are most severely affected by the fh mutation. Within these structures, later-generated neuronal populations are selectively depleted. Together, these results suggest that the flathead gene is essential for a developmental event required for the generation and maturation of late-born cell populations in the brain.

Key words: proliferation; seizures; neural development; neurological mutant; apoptosis; autosomal recessive

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2062295-12$05.00/0

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				J. J. LoTurco, M. R. Sarkisian, L. Cosker, and J. Bai Citron Kinase is a Regulator of Mitosis and Neurogenic Cytokinesis in the Neocortical Ventricular Zone Cereb Cortex, June 1, 2003; 13(6): 588 - 591. [Abstract] [Full Text] [PDF]

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