Department of Biological Sciences, Columbia University, Howard Hughes Medical Institute, New York, New York, United States of America.
Department of Neurobiology, University of Chicago, Chicago, Illinois, United States of America.
PLoS Genet. 2022 Sep 30;18(9):e1010372. doi: 10.1371/journal.pgen.1010372. eCollection 2022 Sep.
Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 14 homeobox genes in 24 distinct neuron classes that are mostly unrelated by location, function and lineage history. 12 of these 24 neuron classes had no homeobox gene function ascribed to them before, while in the other 12 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analyses, 113 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.
同源盒基因是神经元身份的主要调控因子，但它们在动物神经系统中的功能研究程度仍然有限。在秀丽隐杆线虫中，每个神经元类群的特征是由独特的同源盒基因组合表达所定义的，这引发了一个问题，即每个神经元类群是否确实需要一个同源盒基因来正确指定其身份。通过扩展以前对同源盒基因家族成员的突变分析，并描述同源盒基因在秀丽隐杆线虫神经系统不同部位的多种功能，我们在此介绍了在解决这一问题方面的进展。为了研究同源盒基因的功能，我们利用了多种报告基因工具，包括一种新的多色报告基因转座子 NeuroPAL，它允许同时监测整个神经系统中多个分化程序的执行情况。利用这些工具，我们通过在 24 个不同的神经元类群中鉴定 14 个同源盒基因的神经元分化缺陷，为同源盒基因功能的先前特征添加了内容，这些神经元类群在位置、功能和谱系历史上大多没有相关性。在这 24 个神经元类群中，有 12 个以前没有被赋予同源盒基因功能，而在其他 12 个神经元类群中，我们扩展了指定终末分化程序所需的转录因子组合编码。此外，我们证明在特定谱系中，同源盒基因的缺失会导致同源异位性身份转换，并且我们表明这些转换是同源盒编码变化的结果。将目前的分析与过去的分析相结合，现在已知秀丽隐杆线虫的 118 个神经元类群中的 113 个需要同源盒基因来正确执行终末分化程序。这种广泛的部署表明，同源盒基因在神经元身份特化中的功能可能是动物神经系统的一个古老特征。
