tin (tinman) — curation notes

UniProt P22711 (TIN_DROME), FlyBase FBgn0004110. NK-2 class homeodomain transcription factor
(NK-4 / msh-2), the Drosophila ortholog of vertebrate Nkx2-5 (PANTHER PTHR24340:SF41).

Provenance note

Automated deep research failed for this gene (falcon provider returned HTTP 402; OpenAI provider
returned HTTP 401). No *-deep-research-<provider>.md file was created. These notes are a manual
literature synthesis from cached publications (publications/PMID_*.md), PubMed abstracts fetched
into the cache, the UniProt record, and targeted web searches.

Expression and upstream regulation

• First identified as msh-2: expressed in all trunk mesoderm, then restricted to dorsal mesoderm and
  finally to heart precursors PMID:1982429.
• Three successive enhancers; the early one is a direct Twist target PMID:9362473.
• Dorsal restriction/maintenance requires Dpp (Smad) plus Tinman autoregulation at the same enhancer
  PMID:9694800.
• Wg and Dpp intersect with tin-expressing mesoderm to position the heart PMID:12175486.
• In head mesoderm, tin expression is controlled by Notch PMID:21901108.

Loss-of-function phenotypes

• Heart and visceral mesoderm absent; some somatic muscles defective PMID:7915669.
• tin is required for bap activation and hence visceral mesoderm; also heart and specific body wall
  muscle founders [PMID:8101173 "In tin mutant embryos, bap expression is not activated in the dorsal
  mesoderm"; "tin is required for the formation of the heart from dorsal mesoderm and for the
  specification of founder cells for particular body wall muscles"].
• Later, cardioblast-intrinsic Tin is needed for working-myocardium vs ostial identity (represses Doc)
  and for adult heart remodeling PMID:16987868.
• Required for all cardiogenic mesoderm including lymph gland and pericardial nephrocytes
  PMID:15286786.
• Gonadal mesoderm: tin acts in parallel with zfh-1 in dorsolateral mesoderm specification; germ-cell
  migration defects are secondary (PMID:9435287; web review of Moore et al. 1998 / Broihier et al. 1998).
• Corpora cardiaca neuroendocrine cells arise from tin+ head mesoderm and are absent in tin mutants
  PMID:21901108.
• Adult heart function: tin haploinsufficiency interacts with Cdc42; Tin regulates miR-1 PMID:21690310.

Direct targets / molecular mechanism

• Binds TCAAGTG-type NK-2 sites. Direct targets include tinman itself (PMID:9694800), bagpipe
  (PMID:15750188), D-mef2 cardiac enhancer PMID:9034334, pannier
  PMID:11336505,
  Hand (PMID:15975941), even-skipped mesodermal enhancer (PMID:12482712), Toll dorsal vessel
  enhancer (PMID:15870289), eya and stat92E (ChIP-chip, PMID:19217429).
• Cooperates with Pnr/GATA (physical interaction in cultured cells, PMID:11336505), Doc (T-box),
  dTCF and pMad as a "TF collective" on heart enhancers (PMID:22304916).

Master regulator caveat

tin is necessary but not sufficient for heart induction. Ectopic tin alone does not make heart
outside Wg/Dpp intersections (PMID:12175486); synergy with Pannier is needed to induce ectopic
cardial cells PMID:10572044. Similarly, ectopic tin
alone does not expand corpora cardiaca precursors (PMID:21901108). It is best described as a
mesoderm-intrinsic competence/selector factor that combines with signal effectors.

Curation decisions (summary)

• Core: RNA Pol II sequence-specific DNA-binding TF activity (activator) in nucleus; dorsal-mesoderm
  subdivision; cardioblast/cardiac muscle specification and differentiation; visceral mesoderm
  specification via bap.
• Indirect/non-autonomous phenotypes (salivary gland positioning, gut L/R looping, germ cell
  migration, ventral cord FMRFa neuron) marked as over-annotations: tin acts in mesoderm upstream of
  tissues that these processes depend on.
• ARBA IEA "nervous system development" removed (likely transferred from neural NK-2 paralogs such as
  Nkx2-1/Nkx2-2; no evidence tin acts in neural development).
• IEA "digestive tract development" modified to visceral muscle development (GO:0007522).