Cortical thinning and hydrocephalus in mice lacking the immunoglobulin superfamily member CDO.
CDO is a cell surface immunoglobulin superfamily member that positively regulates myogenic differentiation in vitro and in vivo and signals to posttranslationally activate myogenic basic helix-loop-helix (bHLH) transcription factors. The Cdo gene is also expressed in the dorsal aspect and midline structures of the developing central nervous system, and mice lacking CDO on the C57BL/6 background display holoprosencephaly with approximately 80% penetrance, resulting in perinatal lethality. We report here that a fraction of Cdo-/- mice from this background have additional defects in brain development, including hydrocephalus and cortical thinning. Primary neural progenitor cultures from E14.5 Cdo-/- mutants display reduced proliferation, which may underlie the thinning. The cortical preplate and cortices of mutant animals also show reduced staining for beta-tubulin III, indicating defective neuronal differentiation. CDO levels are strongly increased in cultured C17.2 neuronal precursor cells stimulated to differentiate; modulation of CDO levels in these cells by overexpression or interfering RNA approaches enhances or diminishes differentiation, respectively. Cotransfection of CDO enhances the activity of the neurogenic bHLH factor, neurogenin1, in reporter assays and enhances heterodimerization of neurogenin1 and E47. These results indicate that CDO promotes neuronal differentiation and support the hypothesis that CDO coordinates differentiation of multiple cell lineages by regulating the activity of tissue-specific bHLH factors.
Zhang
Wei
W
Brookdale Department of Molecular, Cell, and Developmental Biology, Box 1020, Mount Sinai School of Medicine, New York, New York 10029, USA.
Yi
Min-Jeong
MJ
Chen
Xiaoping
X
Cole
Francesca
F
Krauss
Robert S
RS
Kang
Jong-Sun
JS
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000502:physiology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D003433:Crosses, Genetic; D019281:Dimerization; D005260:Female; D017930:Genes, Reporter; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism; D006720:Homozygote; D006849:Hydrocephalus / Q000235:genetics*; D007136:Immunoglobulins / Q000172:deficiency / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011233:Precipitin Tests; D034622:RNA Interference; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; D007136:Immunoglobulins; D014404:Tubulin; D001616:beta-Galactosidase; C491539:Bhlhe40 protein, mouse; C510744:Cdon protein, mouse