Gene Regulatory Mechanisms Underlying the Spatial and Temporal Regulation of Target-Dependent Gene Expression in Drosophila Neurons

Abstract

Neuronal differentiation often requires target-derived signals from the cells they innervate. These signals typically activate neural subtype-specific genes, but the gene regulatory mechanisms remain largely unknown. Highly restricted expression of the FMRFa neuropeptide in Drosophila Tv4 neurons requires target-derived BMP signaling and a transcription factor code that includes Apterous. Using integrase transgenesis of enhancer reporters, we functionally dissected the Tv4-enhancer of FMRFa within its native cellular context. We identified two essential but discrete cis-elements, a BMP-response element (BMP-RE) that binds BMP-activated pMad, and a homeodomain-response element (HD-RE) that binds Apterous. These cis-elements have low activity and must be combined for Tv4-enhancer activity. Such combinatorial activity is often a mechanism for restricting expression to the intersection of cis-element spatiotemporal activities. However, concatemers of the HD-RE and BMP-RE cis-elements were found to independently generate the same spatiotemporal expression as the Tv4-enhancer. Thus, the Tv4-enhancer atypically combines two low-activity cis-elements that confer the same output from distinct inputs. The activation of target-dependent genes is assumed to 'wait' for target contact. We tested this directly, and unexpectedly found that premature BMP activity could not induce early FMRFa expression; also, we show that the BMP-insensitive HD-RE cis-element is activated at the time of target contact. This led us to uncover a role for the nuclear receptor, seven up (svp), as a repressor of FMRFa induction prior to target contact. Svp is normally downregulated immediately prior to target contact, and we found that maintaining Svp expression prevents cis-element activation, whereas reducing svp gene dosage prematurely activates cis-element activity. We conclude that the target-dependent FMRFa gene is repressed prior to target contact, and that target-derived BMP signaling directly activates FMRFa gene expression through an atypical gene regulatory mechanism.

Molecular Characterization and Expression Profiling of Nuclear Receptor Gene Families in Oriental Fruit Fly, Bactrocera Dorsalis (Hendel)

“…SVP plays an important role in neural development and is involved in the establishment of the central nervous system of D. melanogaster embryos [32], as well as in the proliferation and differentiation of different neuroblasts in later developmental stages [33]. The specific regulatory of SVP indicated that it may repress the induction of the FMRFamide gene prior to target contact [34].…”

Retrograde BMP signaling activates neuronal gene expression through widespread deployment of a conserved BMP-responsivecis-regulatoryactivation element

“…BMP signaling acts via the transcriptional activity of pMad to control neuronal differentiation and synaptic function in Drosophila (9–11,13–15,22,26). BMP signaling plays similarly critical roles throughout vertebrate nervous system development, function and repair (88–94).…”

“…A microarray study reported the differential expression of 101 genes in the late larval CNS of controls and wit mutants, which included twit as well as two other confirmed wit -responsive genes, Pburs and FMRFa (25). These additional genes represent candidate BMP effector genes, although they remain unverified as direct targets of pMad/Medea complexes; only in the cases of FMRFamide ( FMRFa ) and trio has such evidence been provided (24,26). Thus, we still know very little about the direct coordinated gene regulatory processes controlled by BMP signaling and pMad/Medea transcriptional activity that underlies neuronal differentiation, plasticity and synaptic function.…”

Systematic Analysis of Transmitter Coexpression Reveals Organizing Principles of Local Interneuron Heterogeneity

“…DIMMED likely acts in a combinatorial manner with other cell-specific transcription factors to determine peptide expression in individual neurons ( Liu et al, 2016 ; Stratmann and Thor, 2017 ). Although DIMMED does not target any single neuropeptide gene ( Hadzic et al, 2015 ), other transcription factors do regulate subtype-specific neuropeptide expression ( Allan et al, 2003 ; Berndt et al, 2015 ). While DIMMED-positive neurons coexpress multiple peptides, not all peptidergic neurons express DIMMED ( Park et al, 2008a ; Diesner et al, 2018b ), and the role of DIMMED in Manduca has not been established.…”