Mice with Disrupted TGFβ Signaling Have Normal Cerebella Development, but Exhibit Facial Dysmorphogenesis and Strain-Dependent Deficits in Their Body Wall
Mice with Disrupted TGFβ Signaling Have Normal Cerebella Development, but Exhibit Facial Dysmorphogenesis and Strain-Dependent Deficits in Their Body Wall
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DOI：
10.1007/s10571-009-9354-x
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发表时间：
2009-07-01
影响因子：
4
通讯作者：
McLennan, Ian S.
中科院分区：
文献类型：
--
作者：
Asano, Yoshiya;Koishi, Kyoko;McLennan, Ian S.
转化生长因子βS是体外培养的神经元的上下文依赖性调节因子，但其在脑中的生理功能尚不清楚。转化生长因子β1或转化生长因子β2的单倍性不足会导致与年龄相关的神经元退化，但在这两个基因完全缺失的情况下，大脑的发育是正常的。然而，一些带有转化生长因子β受体错义突变的个体是智力低下的，这表明转化生长因子β亚型在脑发育过程中可以相互补偿。这种可能性是通过产生神经元特异性表达的显性负向转化生长因子β信号抑制物小鼠(NSE X PTR)来测试的。具有FVBxC57Bl/6遗传背景的NSE x PTR小鼠尽管有较强的转化生长因子β信号抑制物神经元表达，但仍能正常存活和发育。他们的小脑大小正常，含有正常数量的神经元。当小鼠的遗传背景改变为C57BL/6时，小鼠的表型变为新生儿致死型，新生儿表现出各种畸形。这些畸形与转基因的非神经性表达部位有关，包括面部畸形、腹侧体壁不完全闭合和肠道动力丧失。调节转化生长因子β1(-/-)小鼠表型的C57BL/6 Tgfbm1-3等位基因不是NSE x PTR表型的主要决定因素。这些数据表明，小脑的发育对转化生长因子β信号的水平不敏感，尽管这可能取决于遗传背景。
The transforming growth factor betas (TGF beta s) are context-dependent regulators of neurons in vitro, but their physiological functions in the brain are unclear. Haploinsufficiency of either Tgf beta 1 or Tgf beta 2 leads to age-related deterioration of neurons, but the development of the brain is normal in the full absence of either of these genes. However, some individuals with mis-sense mutations of TGF beta receptors are mentally retarded, suggesting that the TGF beta isoforms can compensate for each other during brain development. This possibility was tested by generating mice (NSE x PTR) with neuron-specific expression of a dominant-negative inhibitor of TGF beta signaling. The NSE x PTR mice with a FVBxC57Bl/6 genetic background were viable and developed normally despite strong neuronal expression of the inhibitor of TGF beta signaling. Their cerebella were of normal size and contained normal numbers of neurons. When the genetic background of the mice was changed to C57BL/6, the phenotype of the mice became neonatal lethal, with the neonates exhibiting various malformations. The malformations correlated with sites of non-neuronal expression of the transgenes and included facial dysmorphogenesis, incomplete closure of the ventral body wall and absence of intestinal motility. The C57BL/6 Tgfbm1-3 alleles, which modulate the phenotype of Tgf beta 1(-/-) mice, were not major determinants of the NSE x PTR phenotype. The data suggest that the development of the cerebellum is insensitive to the level of TGF beta signaling, although this may be dependent on the genetic background.