Cheng Xun, Hsu Ching-mei, Currle D Spencer, Hu Jia Sheng, Barkovich A James, Monuki Edwin S
Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, 92697-4800, USA.
J Neurosci. 2006 Jul 19;26(29):7640-9. doi: 10.1523/JNEUROSCI.0714-06.2006.
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.
顶板是中枢神经系统发育中一个广为人知的信号中心，但其在发育中的端脑和常见的前脑无裂畸形（HPE）中的作用尚不确定。通过对小鼠进行细胞消融实验，我们发现顶板细胞缺失会导致背侧端脑中线诱导失败和HPE。这种形态学表型伴随着中线基因表达的选择性缺陷以及骨形态发生蛋白（Bmps）活性梯度的降低，Bmps是顶板产生的主要信号。在解离细胞和突变外植体中，外源性Bmp4足以模拟顶板在中线基因调控中的选择性，并挽救依赖顶板的中线模式形成。然后在人类HPE患者中证实了小鼠模型预测的先前未被认识的神经解剖学缺陷。这些发现确立了依赖顶板的Bmp信号在背侧端脑模式形成和HPE中的选择性作用，并为人类疾病定义了新的候选基因。
