Defective neural tube closure and anteroposterior patterning in mice lacking the LIM protein LMO4 or its interacting partner deaf-1
Defective neural tube closure and anteroposterior patterning in mice lacking the LIM protein LMO4 or its interacting partner deaf-1
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DOI：
10.1128/mcb.24.5.2074-2082.2004
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发表时间：
2004-03-01
影响因子：
5.3
通讯作者：
Orkin, SH
中科院分区：
文献类型：
--
作者：
Hahm, KM;Sum, EYM;Orkin, SH
LMO 4属于转录调节因子家族，其包含两个锌结合LIM结构域。LIM-only（LMO）蛋白似乎作为其他因子的对接位点，导致多蛋白复合物的组装。转录因子Deaf-1/NUDR已被鉴定为LMO 4的一个伴侣蛋白。我们已经破坏了小鼠中的Lmo 4和Deaf-1基因，以确定它们在体内的生物学功能。所有Lmo 4突变体在出生后不久就死亡，并显示出蝶骨前的缺陷，50%的小鼠还表现出露脑畸形。在Lmo 4缺失的胚胎和新生小鼠中观察到同源异型转化，但具有不完全的同源异型转化。这些包括颈椎和肋骨的骨骼缺陷。此外，在一些Lmo 4（-/-）和Lmo 4（+/-）小鼠中，颅神经IX和X的融合以及颅神经V的缺陷是明显的。值得注意的是，聋人-1突变体表现出类似于Lmo 4突变体中观察到的表型异常。这些包括露脑畸形、颈段变形和肋骨异常。与Lmo 4缺失型小鼠相反，非露脑型耳聋-1突变体保持健康。蝶骨或脑神经没有明显缺陷。因此，Lmo 4和Deaf-1突变小鼠表现出重叠以及不同的表型。我们的数据表明，这两个转录调节因子在影响神经管闭合和骨骼模式的途径中发挥重要作用，最有可能反映它们在体内功能复合物中的存在。
LMO4 belongs to a family of transcriptional regulators that comprises two zinc-binding LIM domains. LIM-only (LMO) proteins appear to function as docking sites for other factors, leading to the assembly of multiprotein complexes. The transcription factor Deaf-1/NUDR has been identified as one partner protein of LMO4. We have disrupted the Lmo4 and Deaf-1 genes in mice to define their biological function in vivo. All Lmo4 mutants died shortly after birth and showed defects within the presphenoid bone, with 50% of mice also exhibiting exencephaly. Homeotic transformations were observed in Lmo4-null embryos and newborn mice, but with incomplete penetrance. These included skeletal defects in cervical vertebrae and the rib cage. Furthermore, fusions of cranial nerves IX and X and defects in cranial nerve V were apparent in some Lmo4(-/-) and Lmo4(+/-) mice. Remarkably, Deaf-1 mutants displayed phenotypic abnormalities similar to those observed in Lmo4 mutants. These included exencephaly, transformation of cervical segments, and rib cage abnormalities. In contrast to Lmo4 nullizygous mice, nonexencephalic Deaf-1 mutants remained healthy. No defects in the sphenoid bone or cranial nerves were apparent. Thus, Lmo4 and Deaf-1 mutant mice exhibit overlapping as well as distinct phenotypes. Our data indicate an important role for these two transcriptional regulators in pathways affecting neural tube closure and skeletal patterning, most likely reflecting their presence in a functional complex in vivo.