Mechanobiology Gene Review Project

Scope

This project reviews genes whose core function is to sense mechanical cues, transmit force-dependent signals, or reshape the mechanical microenvironment in ways that drive reproducible biological outcomes.

This scaffold was informed by cmungall/stuff#671, but the project stays deliberately narrower and more practical than the grant-style framing in that issue:
- focus on reviewable genes, evidence-backed mechanisms, and curation outputs
- use disease relevance to prioritize batches, not to over-claim translational impact
- treat ontology or knowledge-graph follow-up as optional downstream outputs, not the primary deliverable

Operationally, each reviewed gene should be placed in a concrete chain:

mechanical stimulus -> sensor/transducer -> downstream axis -> phenotype/context

Practical inclusion criteria

Include genes when there is evidence for one or more of the following:
- direct sensing of membrane tension, stretch, shear, compression, or osmotic/mechano-osmotic change
- force transmission through adhesions, cortex, cytoskeleton, primary cilium, or nucleus
- robust mechanosensitive downstream signaling repeatedly tied to defined mechanical contexts
- active remodeling of ECM stiffness/compliance or tissue mechanics that is central to the gene's biological role

Deprioritize genes when they are only:
- generic proliferation, migration, or stress-response genes without a defined mechanical trigger
- broad ECM structural components with no mechanotransduction-specific evidence
- one-off assay hits from poorly defined stretching/stiffness systems

Mechanical stimulus space to capture explicitly

• Matrix stiffness / compliance: soft vs stiff substrate responses, durotaxis, fibrotic stiffening
• Fluid shear stress: endothelial flow sensing, tubular flow, ciliary flow detection
• Tensile stretch / cyclic stretch: muscle, lung, vessel wall, epithelium
• Compression / confinement: cartilage, tumor growth, nuclear squeezing during migration
• Membrane tension: channel gating, blebbing, osmotic swelling, cell shape change
• Cell crowding / packing forces: contact-dependent YAP/TAZ control, epithelial jamming
• Topography / curvature: force-sensitive adhesion and cytoskeletal organization

Candidate mechanosensor and transduction modules

1. Direct or near-direct mechanical sensors

• PIEZO1, PIEZO2: canonical mechanically activated ion channels
• TRPV4: osmotic and mechanical channel with recurring roles in cartilage, vasculature, and fibrosis-related signaling
• PKD1, PKD2: flow/ciliary mechanosensation candidates with strong kidney/cilia relevance

2. Adhesion and focal-adhesion force coupling

• ITGB1, ITGA5: integrin-mediated ECM force coupling
• TLN1, VCL, PXN, ILK, PTK2/FAK1: adhesion proteins that convert load-bearing contacts into signaling outputs

3. Cytoskeletal force transmission

• RHOA, ROCK1, ROCK2: contractility and cortical tension axis
• ACTN1, ACTN4, FLNA, MYH9, MYH10: actomyosin-linked mechanical response machinery

4. Nuclear mechanotransmission

• LMNA: nuclear lamina stiffness and force buffering
• SYNE1, SYNE2, SUN1, SUN2, EMD: LINC/nuclear-envelope components transmitting cytoskeletal force to the nucleus

5. Downstream mechanosensitive effectors

• YAP1, WWTR1 (TAZ), LATS1, LATS2: Hippo-linked mechanical state readout
• MAPK1, MAPK3, MTOR, MRTFA, SRF: common downstream axes that often need careful specificity in curation
• SMAD2, SMAD3, TGFB1, CTGF/CCN2: stiffness/fibrosis-linked outputs that should usually be treated as downstream context, not primary sensors

6. Mechanical microenvironment modifiers

• FN1, LOX, COL1A1, SPARC, DCN: ECM regulators that can change tissue stiffness and feed back onto mechanosensing
• These belong in scope only when the mechanical consequence is central, not merely because they are ECM genes

Suggested first review batches

Batch A: canonical direct mechanosensors

• PIEZO1
• PIEZO2
• TRPV4
• PKD1
• PKD2

Batch B: integrin-adhesome force transduction

• ITGB1
• ITGA5
• TLN1
• VCL
• PTK2
• PXN

Batch C: nucleus-cytoskeleton coupling

• LMNA
• SYNE1
• SYNE2
• SUN1
• SUN2
• EMD

Batch D: downstream mechanical state effectors

• YAP1
• WWTR1
• LATS1
• LATS2
• RHOA
• ROCK1
• ROCK2

Batch E: matrix stiffening and fibrosis anchor genes

• FN1
• LOX
• SPARC
• DCN
• TGFB1
• CTGF

Downstream axes to record in reviews

When a gene is in scope, reviewers should try to capture which of these axes is actually supported:
- Ca2+ influx and ion-channel signaling
- RhoA/ROCK-actomyosin contractility
- Hippo/YAP/TAZ nuclear localization or transcriptional output
- FAK/Src/MAPK signaling
- mTOR / growth-state coupling
- TGF-beta / SMAD fibrotic remodeling
- Endothelial flow programs such as KLF2/KLF4/NOS3
- Migration / invasion / EMT-like programs when clearly tied to force context

Disease and tissue anchors for prioritization

These are useful anchors for choosing batches, but should not become hype-driven claims:
- Fibrosis: lung, liver, heart, kidney; matrix stiffening and feed-forward myofibroblast activation
- Cancer invasion and metastasis: confinement, adhesion turnover, ECM remodeling, YAP/TAZ programs
- Cardiovascular and endothelial biology: shear stress, stretch, cardiac remodeling
- Kidney and cilia-linked mechanosensation: flow detection and tubular phenotypes
- Cartilage, bone, tendon, and muscle: load-bearing mechanobiology

Expected outputs

• a reviewed starter set of high-confidence mechanobiology genes in genes/<organism>/<gene>/
• a project-level summary table linking stimulus, sensor/transducer class, downstream axis, and phenotype
• a shortlist of over-annotation patterns or recurrent GO term pain points in mechanobiology curation
• possible pathway-style summary pages once the first review batches stabilize
• optional bioinformatics sidecars only where they answer a concrete curation question

Questions to keep asking during curation

• Is this gene a direct mechanosensor, a force-transducing component, a downstream effector, or a mechanical-context modifier?
• What is the actual stimulus: stiffness, shear, stretch, compression, membrane tension, osmotic change, or something more indirect?
• Is the evidence from a defined mechanical perturbation, or just from a generic migration/adhesion assay?
• Is the reported function likely cell-type or tissue specific?
• Are existing annotations too broad, especially around cell adhesion, ECM organization, actin binding, response to mechanical stimulus, or generic signaling terms?
• Does the paper support a core function, a conditional context-specific role, or only a disease-associated correlation?

Guardrails

• Do not treat every ECM or cytoskeletal gene as mechanobiology by default.
• Do not elevate downstream fibrosis or cancer markers into "mechanosensors" unless the upstream mechanical link is demonstrated.
• Prefer a smaller, well-argued starter set over a sprawling catch-all list.
• Only propose ontology or schema extensions after repeated curation pain points appear across reviewed genes.

How issue #671 influenced this framing

The issue materially improved the scaffold in four ways:

1. It expanded the project from a narrow ECM/stiffness idea into a fuller mechanical landscape including shear, tension, compression, membrane tension, and osmotic pressure.
2. It surfaced a practical shortlist of mechanobiology anchor classes: Piezo channels, integrin/adhesion machinery, nuclear lamins, and YAP/TAZ-linked signaling.
3. It pushed the framing toward explicit stimulus -> sensor -> downstream phenotype chains rather than a flat list of "mechanics-related genes."
4. It suggested useful disease anchors and outputs, especially fibrosis, cancer invasion, and cardiovascular remodeling.

What was intentionally not adopted from the issue as a primary goal:
- a new mechanobiology ontology
- a large AI extraction platform
- broad therapeutic-discovery claims

Those may become relevant later, but the present project is first a grounded curation and synthesis effort for ai-gene-review.

Source input

• Key ideation source: cmungall/stuff issue #671, fetched 2026-04-11