Retrograde BMP signaling activates neuronal gene expression through widespread deployment of a conserved BMP-responsive<i>cis</i>-regulatory<i>activation element</i>

Vuilleumier, Robin; Lian, Tianshun; Flibotte, Stéphane; Khan, Zaynah N; Fuchs, Alisa; Pyrowolakis, George; Allan, Douglas W.

doi:10.1093/nar/gky1135

Cited by 17 publications

(32 citation statements)

References 115 publications

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“…Mad is a transcription factor that regulates the expression of BMP response target genes 93 and has also been shown to play a role in inhibiting synapse formation, as one part of two antagonistic signaling pathways that act together to produce the correct number of synapses 94 . In the Q5 interval of interest (Figure 6e), just two genes are significantly differentially expressed, Odorant-binding protein 28a (Obp28a) and Cyp4d21, neither of which have evidence for a cis eQTL in the King et al 72 dataset.…”

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confidence: 99%

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

Williams-Simon

Posey

Mitchell

et al. 2019

Preprint

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Learning and memory are critical functions for all animals, giving individuals the ability to respond to changes in their environment. Within populations, individuals vary, however the mechanisms underlying this variation in performance are largely unknown. Thus, it remains to be determined what genetic factors cause an individual to have high learning ability and what factors determine how well an individual will remember what they have learned. To genetically dissect learning and memory performance, we used the Drosophila synthetic population resource (DSPR), a multiparent mapping resource in the model system Drosophila melanogaster, consisting of a large set of recombinant inbred lines (RILs) that naturally vary in these and other traits. Fruit flies can be trained in a “heat box” to learn to remain on one side of a chamber (place learning) and can remember this (place memory) over short timescales. Using this paradigm, we measured place learning and memory for ~49 000 individual flies from over 700 DSPR RILs. We identified 16 different loci across the genome that significantly affect place learning and/or memory performance, with 5 of these loci affecting both traits. To identify transcriptomic differences associated with performance, we performed RNA‐Seq on pooled samples of seven high performing and seven low performing RILs for both learning and memory and identified hundreds of genes with differences in expression in the two sets. Integrating our transcriptomic results with the mapping results allowed us to identify nine promising candidate genes, advancing our understanding of the genetic basis underlying natural variation in learning and memory performance.

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confidence: 99%

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

Williams-Simon

Posey

Mitchell

et al. 2019

Preprint

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“…While these genes are not significantly differentially expressed between the memory cohorts, the trend is in the same direction in the learning cohorts for both genes (Mad: log 2 FC: −0.13, P adj = 0.67; Hydr2: log 2 FC = −0.19, P adj = 0.45). Mad is a transcription factor that regulates the expression of BMP response target genes 93 and has also been shown to play a role in inhibiting synapse formation, as one part of two antagonistic signaling pathways that act together to produce the correct number of synapses. 94 In the Q5 interval of interest ( Figure 6E), just two genes are significantly differentially expressed, Odorant-binding protein 28a (Obp28a) and…”

Section: Identification Of Candidate Genesmentioning

confidence: 99%

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

Williams-Simon

Posey

Mitchell

et al. 2019

Genes Brain and Behavior

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Learning and memory are critical functions for all animals, giving individuals the ability to respond to changes in their environment. Within populations, individuals vary, however the mechanisms underlying this variation in performance are largely unknown. Thus, it remains to be determined what genetic factors cause an individual to have high learning ability and what factors determine how well an individual will remember what they have learned. To genetically dissect learning and memory performance, we used the Drosophila synthetic population resource (DSPR), a multiparent mapping resource in the model system Drosophila melanogaster, consisting of a large set of recombinant inbred lines (RILs) that naturally vary in these and othertraits. Fruit flies can be trained in a "heat box" to learn to remain on one side of a chamber (place learning) and can remember this (place memory) over short timescales. Using this paradigm, we measured place learning and memory for~49 000 individual flies from over 700 DSPR RILs. We identified 16 different loci across the genome that significantly affect place learning and/or memory performance, with 5 of these loci affecting both traits. To identify transcriptomic differences associated with performance, we performed RNA-Seq on pooled samples of seven high performing and seven low performing RILs for both learning and memory and identified hundreds of genes with differences in expression in the two sets. Integrating our transcriptomic results with the mapping results allowed us to identify nine promising candidate genes, advancing our understanding of the genetic basis underlying natural variation in learning and memory performance.K E Y W O R D S differential gene expression, Drosophila melanogaster, learning, memory, multiparental population, QTL

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“…In postmitotic neurons, retrograde signaling continues to play prominent roles during neuronal maturation and through life in regulating terminal differentiation and synaptic function ( Allan et al, 2003 ; Angley et al, 2003 ; Veverytsa and Allan, 2011 ; Berke et al, 2013 ; Chou et al, 2013 ; Kelly et al, 2013 ; Majdazari et al, 2013 ; Xiao et al, 2013 ; DuVal et al, 2014 ; McCabe et al, 2003 ; Guha et al, 2004 ; Lopez-Coviella et al, 2005 ; Hodge et al, 2007 ; Pavelock et al, 2007 ; Miguel-Aliaga et al, 2008 ; Eade and Allan, 2009 ; Henríquez et al, 2011 ). In Drosophila , retrograde BMP signaling occurs within most efferent neurons, regulating a diverse suite of target genes in a subtype-specific manner; for example, the neuropeptide genes unique to each neurosecretory subtype, and the partially overlapping battery of genes that support the growth and strengthening of motor neuron neuromuscular junction synapses ( Veverytsa and Allan, 2011 ; Miguel-Aliaga et al, 2008 ; Allan et al, 2003 ; Kim and Marqués, 2010 ; Vuilleumier et al, 2019 ; Ball et al, 2010 ; Marqués et al, 2003 ). An unresolved question regards how BMP target genes are differentially specified within each of these BMP-activated neuron subtypes.…”

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated that the BMP-AE motif serves as a widely-deployed BMP-dependent activator of gene expression in larval Drosophila efferent neurons ( Vuilleumier et al, 2019 ). In that study, BMP-AE motifs were shown to confer BMP-dependence on enhancers that were active in diverse patterns across the many subtypes of efferent neurons.…”

Section: Introductionmentioning

confidence: 99%

A low affinity cis-regulatory BMP response element restricts target gene activation to subsets of Drosophila neurons

Berndt

Othonos

Lian

et al. 2020

eLife

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Retrograde BMP signaling and canonical pMad/Medea-mediated transcription regulates diverse target genes across subsets of Drosophila efferent neurons, to differentiate neuropeptidergic neurons and promote motor neuron terminal maturation. How a common BMP signal regulates diverse target genes across neuronal subsets remains largely unresolved, although available evidence implicates subset-specific transcription factor codes rather than differences in BMP signaling. Here, we examine the cis-regulatory mechanisms restricting BMP-induced FMRFa neuropeptide expression to Tv4 neurons. We find that pMad/Medea bind at an atypical, low affinity motif in the FMRFa enhancer. Converting this motif to high affinity caused ectopic enhancer activity and eliminated Tv4 neuron expression. In silico searches identified additional motif instances functional in other efferent neurons, implicating broader functions for this motif in BMP-dependent enhancer activity. Thus, differential interpretation of a common BMP signal, conferred by low affinity pMad/Medea binding motifs, can contribute to the specification of BMP target genes in efferent neuron subsets.

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

Cited by 17 publications

References 115 publications

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

Multiple genetic loci affect place learning and memory performance in Drosophila melanogaster

A low affinity cis-regulatory BMP response element restricts target gene activation to subsets of Drosophila neurons

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