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

Berndt, Anthony; Othonos, Katerina M; Lian, Tianshun; Flibotte, Stéphane; Miao, Mo; Bhuiyan, Shamsuddin A.; Cho, Raymond Y.; Fong, Justin S; Hur, Seo Am; Pavlidis, Paul; Allan, Douglas W.

doi:10.7554/elife.59650

Cited by 3 publications

(3 citation statements)

References 81 publications

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“…Although there is good evidence that pMad accumulates around presynaptic active zones with the removal of postsynaptic FMRP ( Song et al, 2022 ), the mechanism by which pMad is induced and works with other interactors to regulate synaptogenesis remains to be studied. Since pMad is well-known to work with the cofactor Medea (Med) to serve as a transcription factor ( Berndt et al, 2020 ), it would be interesting to map gene expression related to synaptic development modulated by presynaptic pMad-Med interaction following targeted postsynaptic knockdown of FMRP.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Song

Broadie²

2022

Front. Cell Dev. Biol.

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Drosophila models of neurological disease contribute tremendously to research progress due to the high conservation of human disease genes, the powerful and sophisticated genetic toolkit, and the rapid generation time. Fragile X syndrome (FXS) is the most prevalent heritable cause of intellectual disability and autism spectrum disorders, and the Drosophila FXS disease model has been critical for the genetic screening discovery of new intercellular secretion mechanisms. Here, we focus on the roles of three major signaling pathways: BMP, Wnt, and insulin-like peptides. We present Drosophila FXS model defects compared to mouse models in stem cells/embryos, the glutamatergic neuromuscular junction (NMJ) synapse model, and the developing adult brain. All three of these secreted signaling pathways are strikingly altered in FXS disease models, giving new mechanistic insights into impaired cellular outcomes and neurological phenotypes. Drosophila provides a powerful genetic screening platform to expand understanding of these secretory mechanisms and to test cellular roles in both peripheral and central nervous systems. The studies demonstrate the importance of exploring broad genetic interactions and unexpected regulatory mechanisms. We discuss a number of research avenues to pursue BMP, Wnt, and insulin signaling in future FXS investigations and the development of potential therapeutics.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Song

Broadie²

2022

Front. Cell Dev. Biol.

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“…When the axon reaches the DNH, it receives the TGFβ/BMP ligand Glass bottom boat (Gbb), which binds to a hetero-tetrameric receptor complex consisting of two receptor pairs: the type I (Saxophone; Sax and Thick veins; Tkv) and type II (Wishful thinking; Wit) BMP receptors [ 6 , 30 , 31 ]. When activated, this complex results in the phosphorylation of Mad [ 32 , 33 ], triggering the expression of the FMRFa neuropeptide gene [ 34 , 35 ]. Interestingly, while the majority of Ap cluster determinants were unperturbed, we observed loss of pMad staining in the Ap cluster neurons in Mcm5 mutants ( Fig 2I and 2J ).…”

Section: Resultsmentioning

confidence: 99%

Selective role of the DNA helicase Mcm5 in BMP retrograde signaling during Drosophila neuronal differentiation

et al. 2022

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The MCM2-7 complex is a highly conserved hetero-hexameric protein complex, critical for DNA unwinding at the replicative fork during DNA replication. Overexpression or mutation in MCM2-7 genes is linked to and may drive several cancer types in humans. In mice, mutations in MCM2-7 genes result in growth retardation and mortality. All six MCM2-7 genes are also expressed in the developing mouse CNS, but their role in the CNS is not clear. Here, we use the central nervous system (CNS) of Drosophila melanogaster to begin addressing the role of the MCM complex during development, focusing on the specification of a well-studied neuropeptide expressing neuron: the Tv4/FMRFa neuron. In a search for genes involved in the specification of the Tv4/FMRFa neuron we identified Mcm5 and find that it plays a highly specific role in the specification of the Tv4/FMRFa neuron. We find that other components of the MCM2-7 complex phenocopies Mcm5, indicating that the role of Mcm5 in neuronal subtype specification involves the MCM2-7 complex. Surprisingly, we find no evidence of reduced progenitor proliferation, and instead find that Mcm5 is required for the expression of the type I BMP receptor Tkv, which is critical for the FMRFa expression. These results suggest that the MCM2-7 complex may play roles during CNS development outside of its well-established role during DNA replication.

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“…2008 ). Although Tv4 neuron subtype gene expression involves combinatorial regulation with neuron-specific transcription factors, it contains an exceptionally low affinity Mad/Medea binding site ( Berndt et al . 2020 ).…”

Section: Regulation Of Bmp Signalingmentioning

confidence: 99%

Bone morphogenetic protein signaling: the pathway and its regulation

Akiyama,

Raftery,

Wharton

2023

Genetics

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In the mid-1960s, bone morphogenetic proteins (BMPs) were first identified in the extracts of bone to have the remarkable ability to induce heterotopic bone. When the Drosophila gene decapentaplegic (dpp) was first identified to share sequence similarity with mammalian BMP2/BMP4 in the late-1980s, it became clear that secreted BMP ligands can mediate processes other than bone formation. Following this discovery, collaborative efforts between Drosophila geneticists and mammalian biochemists made use of the strengths of their respective model systems to identify BMP signaling components and delineate the pathway. The ability to conduct genetic modifier screens in Drosophila with relative ease was critical in identifying the intracellular signal transducers for BMP signaling and the related transforming growth factor-beta/activin signaling pathway. Such screens also revealed a host of genes that encode other core signaling components and regulators of the pathway. In this review, we provide a historical account of this exciting time of gene discovery and discuss how the field has advanced over the past 30 years. We have learned that while the core BMP pathway is quite simple, composed of 3 components (ligand, receptor, and signal transducer), behind the versatility of this pathway lies multiple layers of regulation that ensures precise tissue-specific signaling output. We provide a sampling of these discoveries and highlight many questions that remain to be answered to fully understand the complexity of BMP signaling.

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

Cited by 3 publications

References 81 publications

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

Selective role of the DNA helicase Mcm5 in BMP retrograde signaling during Drosophila neuronal differentiation

Bone morphogenetic protein signaling: the pathway and its regulation

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