Central roles of the roof plate in telencephalic development and holoprosencephaly.
The roof plate is a well known signaling center in CNS development, but its roles in the developing telencephalon and the common holoprosencephaly (HPE) malformation have been uncertain. Using cellular ablations in mice, we show that roof plate cell loss causes failed midline induction and HPE in the dorsal telencephalon. This morphologic phenotype is accompanied by selective deficits in midline gene expression and a reduced activity gradient for bone morphogenetic proteins (Bmps), the major signals produced by the roof plate. In dissociated cells and mutant explants, exogenous Bmp4 is sufficient to mimic roof plate selectivity in midline gene regulation and to rescue roof plate-dependent midline patterning. Previously unrecognized neuroanatomical defects predicted by the mouse model are then confirmed in human HPE patients. These findings establish selective roles for roof plate-dependent Bmp signaling in dorsal telencephalic patterning and HPE and define novel candidate genes for the human disorder.
Cheng
Xun
X
Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, 92697-4800, USA.
Hsu
Ching-mei
CM
Currle
D Spencer
DS
Hu
Jia Sheng
JS
Barkovich
A James
AJ
Monuki
Edwin S
ES
D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000196:embryology; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D016142:Holoprosencephaly / Q000209:etiology* / Q000235:genetics; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009420:Nervous System / Q000196:embryology*; D009436:Neural Tube Defects / Q000150:complications* / Q000235:genetics; D010641:Phenotype; D013687:Telencephalon / Q000196:embryology*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D014157:Transcription Factors