Doublecortin is required in mice for lamination of the hippocampus but not the neocortex.
Doublecortin (DCX) is a microtubule-associated protein that is required for normal neocortical and hippocampal development in humans. Mutations in the X-linked human DCX gene cause gross neocortical disorganization (lissencephaly or "smooth brain") in hemizygous males, whereas heterozygous females show a mosaic phenotype with a normal cortex as well as a second band of misplaced (heterotopic) neurons beneath the cortex ("double cortex syndrome"). We created a mouse carrying a targeted mutation in the Dcx gene. Hemizygous male Dcx mice show severe postnatal lethality; the few that survive to adulthood are variably fertile. Dcx mutant mice show neocortical lamination that is largely indistinguishable from wild type and show normal patterns of neocortical neurogenesis and neuronal migration. In contrast, the hippocampus of both heterozygous females and hemizygous males shows disrupted lamination that is most severe in the CA3 region. Behavioral tests show defects in context and cued conditioned fear tests, suggesting that deficits in hippocampal learning accompany the abnormal cytoarchitecture.
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Joseph C
JC
Corbo
Thomas A
TA
Deuel
Jeffrey M
JM
Long
Patricia
P
LaPorte
Elena
E
Tsai
Anthony
A
Wynshaw-Boris
Christopher A
CA
Walsh
D000818:Animals; D001522:Behavior, Animal; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005239:Fear; D005260:Female; D005328:Fetal Viability; D018390:Gene Targeting; D017930:Genes, Reporter; D006579:Heterozygote; D006624:Hippocampus / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology*; D007858:Learning; D008297:Male; D008568:Memory; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity; D019579:Neocortex / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology*; D009421:Nervous System Malformations / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011930:Reaction Time
C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides