Magnetic resonance imaging and histological studies of corpus callosal and hippocampal abnormalities linked to doublecortin deficiency.
Mutated doublecortin (DCX) gives rise to severe abnormalities in human cortical development. Adult Dcx knockout mice show no major neocortical defects but do have a disorganized hippocampus. We report here the developmental basis of these hippocampal abnormalities. A heterotopic band of neurons was identified starting at E17.5 in the CA3 region and progressing throughout the CA1 region by E18.5. At neonatal stages, the CA1 heterotopic band was reduced, but the CA3 band remained unchanged, continuing into adulthood. Thus, in mouse, migration of CA3 neurons is arrested during development, whereas CA1 cell migration is retarded. On the Sv129Pas background, magnetic resonance imaging (MRI) also suggested abnormal dorsal hippocampal morphology, displaced laterally and sometimes rostrally and associated with medial brain structure abnormalities. MRI and cryosectioning showed agenesis of the corpus callosum in Dcx knockout mice on this background and an intermediate, partial agenesis in heterozygote mice. Wild-type littermates showed no callosal abnormalities. Hippocampal and corpus callosal abnormalities were also characterized in DCX-mutated human patients. Severe hippocampal hypoplasia was identified along with variable corpus callosal defects ranging from total agenesis to an abnormally thick or thin callosum. Our data in the mouse, identifying roles for Dcx in hippocampal and corpus callosal development, might suggest intrinsic roles for human DCX in the development of these structures.
Kappeler
Caroline
C
Département de Génétique et Développement, Institut Cochin, F-75014 Paris, France.
Dhenain
Marc
M
Phan Dinh Tuy
Françoise
F
Saillour
Yoann
Y
Marty
Serge
S
Fallet-Bianco
Catherine
C
Souville
Isabelle
I
Souil
Evelyne
E
Pinard
Jean-Marc
JM
Meyer
Gundela
G
Encha-Razavi
Ferechté
F
Volk
Andreas
A
Beldjord
Cherif
C
Chelly
Jamel
J
Francis
Fiona
F
D037881:Aborted Fetus; D061085:Agenesis of Corpus Callosum; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002828:Choristoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006624:Hippocampus / Q000002:abnormalities*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics*
C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides