Selective disruption of synaptic BMP signaling by a smad mutation adjacent to the highly conserved H2 helix

Tho Huu Nguyen, Tae Hee Han, Stuart J. Newfeld, Mihaela Serpe

Research output: Contribution to journalArticlepeer-review

Abstract

Bone morphogenetic proteins (BMPs) shape normal development and function via canonical and noncanonical signaling pathways. BMPs initiate canonical signaling by binding to transmembrane receptors that phosphorylate Smad proteins and induce their translocation into the nucleus and regulation of target genes. Phosphorylated Smads also accumulate at cellular junctions, but this noncanonical, local BMP signaling modality remains less defined. We have recently reported that phosphorylated Smad (pMad in Drosophila) accumulates at synaptic junctions in protein complexes with genetically distinct composition and regulation. Here, we examined a wide collection of Drosophila Mad alleles and searched for molecular features relevant to pMad accumulation at synaptic junctions. We found that strong Mad alleles generally disrupt both synaptic and nuclear pMad, whereas moderate Mad alleles have a wider range of phenotypes and can selectively impact different BMP signaling pathways. Interestingly, regulatory Mad mutations reveal that synaptic pMad appears to be more sensitive to a net reduction in Mad levels than nuclear pMad. Importantly, a previously uncharacterized allele, Mad8, showed markedly reduced synaptic pMad but only moderately diminished nuclear pMad. The postsynaptic composition and electrophysiological properties of Mad8 neuromuscular junctions (NMJs) were also altered. Using biochemical approaches, we examined how a single point mutation in Mad8 could influence the Mad-receptor interface and identified a key motif, the H2 helix. Our study highlights the biological relevance of Smad-dependent, synaptic BMP signaling and uncovers a highly conserved structural feature of Smads, critical for normal development and function.

Original languageEnglish (US)
Pages (from-to)159-175
Number of pages17
JournalGenetics
Volume216
Issue number1
DOIs
StatePublished - Sep 2020

Keywords

  • BMP signaling
  • Drosophila NMJ
  • Mad alleles

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Selective disruption of synaptic BMP signaling by a smad mutation adjacent to the highly conserved H2 helix'. Together they form a unique fingerprint.

Cite this