Abstract：
Paralog factors are considered to ensure the robustness of biological processes by providing redundant activity in cells where they are co-expressed. However, the specific contribution of each factor is frequently underestimated. In the developing spinal cord, multiple families of transcription factors successively contribute to differentiate an initially homogenous population of neural progenitors into a myriad of neuronal subsets with distinct molecular, morphological, and functional characteristics. The LIM-homeodomain transcription factors Lhx3, Lhx4, Isl1 and Isl2 promote the segregation and differentiation of spinal motor neurons and V2 interneurons. Based on their high sequence identity and their similar distribution, the Lhx3 and Lhx4 paralogs are considered to contribute similarly to these processes. However, the specific contribution of Lhx4 has never been studied. Here, we provide evidence that Lhx3 and Lhx4 are present in the same cell populations during spinal cord development. Similarly to Lhx3, Lhx4 can form multiproteic complexes with Isl1 or Isl2 and the nuclear LIM interactor NLI. Lhx4 can stimulate a V2-specific enhancer more efficiently than Lhx3 and surpasses Lhx3 in promoting the differentiation of V2a interneurons in chicken embryo electroporation experiments. Finally, Lhx4 inactivation in mice results in alterations of differentiation of the V2a subpopulation, but not of motor neuron production, suggesting that Lhx4 plays unique roles in V2a differentiation that are not compensated by the presence of Lhx3. Thus, Lhx4 could be the major LIM-HD factor involved in V2a interneuron differentiation during spinal cord development and should be considered for in vitro differentiation of spinal neuronal populations.
摘要：
模拟因子被认为通过在它们共表达的细胞中提供冗余活性来确保生物过程的稳健性。然而,每个因素的具体贡献经常被低估。在发育中的脊髓中，多个转录因子家族相继有助于将最初同质的神经祖细胞群分化为无数具有不同分子的神经元亚群，形态学,和功能特征。LIM-同源结构域转录因子Lhx3，Lhx4，Isl1和Isl2促进脊髓运动神经元和V2中间神经元的分离和分化。基于它们的高序列同一性和相似的分布，Lhx3和Lhx4旁系同源物被认为对这些过程有类似的贡献。然而,Lhx4的具体贡献从未被研究过。这里,我们提供的证据表明Lhx3和Lhx4在脊髓发育过程中存在于相同的细胞群中.与Lhx3相似，Lhx4可以与Isl1或Isl2和核LIM相互作用子NLI形成多蛋白质复合物。在鸡胚电穿孔实验中，Lhx4可以比Lhx3更有效地刺激V2特异性增强子，并且在促进V2a中间神经元分化方面超过Lhx3。最后,小鼠Lhx4失活导致V2a亚群分化的改变，但不是运动神经元的产生，这表明Lhx4在V2a分化中起着独特的作用，而Lhx3的存在不能补偿。因此，Lhx4可能是脊髓发育过程中参与V2a中间神经元分化的主要LIM-HD因子，应考虑用于脊髓神经元群体的体外分化。
