spz5 (DNT2, NT2; UniProtKB:Q9VZX1) curation notes

Literature search (2026-11-06)

No deep-research API keys were available, so just deep-research was not run. The FlyBase
hand-written description (spz5-deep-research-flybase.md) was checked claim by claim. Papers
read from the local cache (full text unless stated): PMID:19018662, PMID:23892553,
PMID:24124519, PMID:28373203, PMID:28846707, PMID:31088910, PMID:30361090 (abstract only),
PMID:30745142, PMID:39704728, PMID:42552905.

Identity

• Spätzle-family cystine-knot protein; signal peptide 1-29, pro-domain 30-284, mature chain
  285-387 (UniProt FT). Readily cleaved by furin before secretion [PMID:23892553 "whereas DNT2 is
  consistently secreted from S2 cells as a mature, cleaved form consisting of the cystine-knot
  domain"; PMID:28373203 "DNT1 and 2 are cleaved intracellularly by conserved furins."].
• PANTHER PTHR23199:SF16; PAINT node PTN002354018. No PAINT IRD/IKR losses on the lineage.

Receptors

• Toll-6 and Toll-7 PMID:23892553; purified DNT2 triggers Dif signalling via
  Toll-6/7 in S2 cells PMID:23892553.
• Kek-6 (truncated Trk-like) PMID:28846707.
• Toll-2 by genetic interaction in the visual system PMID:42552905.
• Toll-1: Spz5 is a Toll-1 ligand independent of furin processing, and Spz5 accounts for most
  Toll-1 ligand activity of larval extract PMID:30361090. Also
  in vitro Toll-1/Toll-7 binding and drosomycin activation PMID:31088910.
• Glia: apoptotic neurons process Spz5, which activates a dSARM-dependent Toll-6 pathway in glia
  that induces Draper PMID:30745142.

Biological roles

• Neuronal survival, redundantly with DNT1 PMID:19018662; via Toll-6 PMID:23892553; PAM dopaminergic neurons via Toll-6
  PMID:39704728.
• Motor axon targeting, mild PMID:19018662.
• Structural synaptic plasticity at the NMJ (retrograde, muscle-derived, with Kek-6 and Toll-6)
  PMID:28846707 and
  in an adult dopaminergic circuit PMID:39704728.
• Behaviour: larval crawling (PMID:28846707), adult locomotion and long-term memory
  PMID:39704728.

FlyBase description check

All claims traced: paralog of spz (PTHR23199; PMID:19018662); ligand of Toll-6 and kek6
(PMID:23892553, PMID:28846707); survival, axonal/dendritic growth and branching, synaptic
structural plasticity (PMID:28846707, PMID:39704728); larval locomotion (PMID:28846707) and adult
locomotion and long-term memory (PMID:39704728). Incomplete (omits Toll-7, Toll-1, Toll-2) but not
wrong -> VERIFIED.

Decisions summary

• MF core: growth factor activity (GO:0008083); Toll binding rows MODIFY (ligand convention).
• BP core: NEW neurotrophin signaling pathway (GO:0038179); negative regulation of neuron
  apoptotic process; regulation of synaptic plasticity.
• Toll-1 (immune) Toll signaling pathway, innate immune response and AMP production rows are
  supported by two labs (PMID:30361090, PMID:31088910) and kept as non-core.