Tissue-specific transcription of the neuronal gene Lim3 affects Drosophila melanogaster lifespan and locomotion

Abstract

The identity of neuronal cell types is established and maintained by the expression of neuronal genes coding for ion channels, neurotransmitters, and neuropeptides, among others. Some of these genes have been shown to affect lifespan; however, their role in lifespan control remains largely unclear. The Drosophila melanogaster gene Lim3 encodes a transcription factor involved in complicated motor neuron specification networks. We previously identified Lim3 as a candidate gene affecting lifespan. To obtain direct evidence of the involvement of Lim3 in lifespan control, Lim3 overexpression and RNAi knockdown were induced in the nervous system and muscles of Drosophila using the GAL4-UAS binary system. We demonstrated that Lim3 knockdown in the nervous system increased survival at an early age and that Lim3 knockdown in muscles both increased survival at an early age and extended median lifespan, directly establishing the involvement of Lim3 in lifespan control. Lim3 overexpression in nerves and muscles was deleterious and led to lethality and decreased lifespan, respectively. Lim3 misexpression in both nerves and muscles increased locomotion regardless of changes in lifespan, which indicated that the effects of Lim3 on lifespan and locomotion can be uncoupled. Decreased synaptic activity was observed in the neuromuscular junctions of individuals with Lim3 overexpression in muscles, in association with decreased lifespan. However, no changes in NMJ activity were associated with the positive shift in locomotion observed in all misexpression genotypes. Our data suggested that modifications in the microtubule network may be induced by Lim3 misexpression in muscles and cause an increase in locomotion.

Reduced Neuronal Transcription of Escargot, the Drosophila Gene Encoding a Snail-Type Transcription Factor, Promotes Longevity

“…A rather specific suggestion that an intermediate level of esg transcription in the nervous system is the most beneficial for longevity might account for the results we obtained. A similar hypothesis explained our data on the effects of Lim3 expression on life span (Rybina and Pasyukova, 2010 ; Rybina et al, 2017 ). Unfortunately, the level of esg expression both in the central nervous system (heads) and peripheral nervous system (carcasses) of adult flies is extremely low ( http://flybase.org/reports/FBgn0001981.html ), which makes the direct evaluation of the knockdown effects in these tissues with a precision necessary for statistically reliable comparisons rather tricky.…”

“…hs = GawB}elav C155 w 1118 ; P{w + mC = UAS-Dcr-2.D}2 line was used to induce the expression of transgenic constructs in the nervous system. This driver line proved to be effective in our previous work, according to the real time RT-qPCR data (Rybina et al, 2017 ; Symonenko, unpublished results).…”

“…Transcription factors such as FOXO, HSF-1, HIF-1, NFkB, TFEB, and others participate in different signaling cascades and are crucial for the regulation of longevity and aging (for reviews see Alcedo et al, 2013 ; Bhatt and Ghosh, 2014 ; Lapierre et al, 2015 ). Previously, we demonstrated that two genes, shuttle craft and Lim3 , which encode transcription factors involved in the development of the nervous system, affect Drosophila life span (Pasyukova et al, 2004 ; Roshina et al, 2014 ; Rybina et al, 2017 ). New data from this study adds one more gene to this list.…”

“…By directly establishing the involvement of the neuronal function of esg in life span control, we have progressed toward achieving our main goal: to set a collection of genes encoding neuronal transcription factors involved in the life span control. This collection now includes shuttle craft (Roshina et al, 2014 ), Lim3 (Rybina et al, 2017 ) and esg and will be further used for analysis of molecular mechanisms underlying aging.…”

“…We have already demonstrated that several genes that encode RNA polymerase II transcription factors and that are involved in neural development affect life span in Drosophila melanogaster (Pasyukova et al, 2004 ; Rybina and Pasyukova, 2010 ; Roshina et al, 2014 ; Rybina et al, 2017 ). Among other genes, escargot ( esg ) was identified as a candidate gene affecting life span in a screen of more than 1,500 insertion mutations and the insertion located downstream of esg was further confirmed to be causally associated with life span control (Magwire et al, 2010 ).…”