The Evolutionarily Conserved LIM Homeodomain Protein LIM-4/LHX6 Specifies the Terminal Identity of a Cholinergic and Peptidergic C. elegans Sensory/Inter/Motor Neuron-Type

摘要

The expression of specific transcription factors determines the differentiated features of postmitotic neurons. However, the mechanism by which specific molecules determine neuronal cell fate and the extent to which the functions of transcription factors are conserved in evolution are not fully understood. In C . elegans , the cholinergic and peptidergic SMB sensory/inter/motor neurons innervate muscle quadrants in the head and control the amplitude of sinusoidal movement. Here we show that the LIM homeobox protein LIM-4 determines neuronal characteristics of the SMB neurons. In lim-4 mutant animals, expression of terminal differentiation genes, such as the cholinergic gene battery and the flp-12 neuropeptide gene, is completely abolished and thus the function of the SMB neurons is compromised. LIM-4 activity promotes SMB identity by directly regulating the expression of the SMB marker genes via a distinct cis -regulatory motif. Two human LIM-4 orthologs, LHX6 and LHX8, functionally substitute for LIM-4 in C . elegans . Furthermore, C . elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in the human neuronal cell lines. Our results indicate that the evolutionarily conserved LIM-4/LHX6 homeodomain proteins function in generation of precise neuronal subtypes. Author Summary The correct generation and maintenance of the nervous system is critical for the animal’s life. Dysregulation of these processes leads to multiple neurodevelopmental disorders. It has been a daunting challenge not only to identify the developmental mechanisms that determine neuronal cell fate, but also to understand the extent to which the mechanisms are evolutionarily conserved. Here, we describe a developmental mechanism that determines the fate of a specific cholinergic and peptidergic neuronal type in C . elegans . We show that the lim-4 LIM homeodomain transcription factor is necessary and sufficient to promote and maintain the specific cholinergic and peptidergic properties and functions via binding to unique DNA sequences. We also demonstrate that C . elegans lim-4 and human LHX6 show striking functional similarity; specifically, C . elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in human neuronal cell lines. Given the high conservation of these transcription factors, these developmental mechanisms are likely to be generally applicable in the nervous system of other organisms as well.