Central roles of the roof plate in telencephalic development and holoprosencephaly
Central roles of the roof plate in telencephalic development and holoprosencephaly
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DOI：
10.1523/jneurosci.0714-06.2006
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发表时间：
2006-07-19
影响因子：
5.3
通讯作者：
Monuki, Edwin S.
中科院分区：
文献类型：
--
作者：
Cheng, Xun;Hsu, Ching-mei;Monuki, Edwin S.
顶板是中枢神经系统发育的信号中枢，但其在端脑发育和常见的前脑无裂畸形（HPE）中的作用尚不清楚。使用细胞消融小鼠，我们表明，顶板细胞损失导致失败的中线诱导和HPE在背侧端脑。这种形态学表型伴随着中线基因表达的选择性缺陷和骨形态发生蛋白（Bmps）活性梯度的降低，Bmps是顶板产生的主要信号。在分离的细胞和突变体外植体，外源性Bmp4是足以模拟屋顶板中线基因调控的选择性和拯救屋顶板依赖中线图案。以前未被识别的神经解剖缺陷预测的小鼠模型，然后在人类HPE患者中得到证实。这些发现建立了屋顶板依赖性BMP信号在背侧端脑模式和HPE中的选择性作用，并为人类疾病定义了新的候选基因。
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.