Hedgehog Signaling Tournament
Two onboarding diagrams orient you in Hedgehog signaling. Then eight MCAT-DoK quiz rounds: Patched as the receptor, Smoothened activation, primary-cilium-dependent signaling, GLI transcription factors, vismodegib + sonidegib in basal cell carcinoma, Gorlin syndrome, and holoprosencephaly / cyclopamine.
Where the Signaling by Hedgehog fits in Signal Transduction
Hedgehog is one of the eight major Reactome 'Signal Transduction' branches and a master regulator of embryonic patterning (limb axis, neural tube, midline forebrain). It uses an unusual 'inhibitor of an inhibitor' logic: Patched holds Smoothened off until Hedgehog binds. Click the highlighted Hedgehog box to enter the tournament.
Click the highlighted Signaling by Hedgehog box to continue.
What this tournament tests
Each task maps to a distinct MCAT cognitive demand. The first two orient you in the broader topology; the next eight test the high-yield mechanism, regulation, sequence and quantitative reasoning that consistently appear on test day.
The Bigger Picture
Anchor Hedgehog signaling within the Reactome Signal Transduction overview alongside Wnt and Notch developmental pathways.
Whole-Pathway Overview
Pan and zoom the curated WikiPathways Hedgehog pathway figure before answering questions.
Fill in the Blank
Recall that Patched (PTCH1) inhibits Smoothened (SMO) in the absence of Hedgehog ligand.
Vismodegib Disruptor
Predict why vismodegib targets SMO in basal cell carcinoma despite the genetic lesion being upstream in Patched.
Sequence Ordering
Order SHH binding -> Patched internalization -> SMO activation in the primary cilium -> GLI-A release -> nuclear gene activation.
Match the Pairs
Pair SHH, Patched, SMO, SUFU, GLI, vismodegib, and cyclopamine with their precise pathway roles.
Numeric Input
Count the transmembrane domains of Smoothened (7TM).
Select All That Apply
Identify true statements about primary cilium signaling, adult Hedgehog activity, and PTCH1 loss in Gorlin syndrome.
Odd One Out
Distinguish Hedgehog components from TCF/LEF transcription factors of the Wnt pathway.
Holoprosencephaly Disruptor
Predict why SHH loss-of-function causes failed forebrain bisection and midline craniofacial defects.
Public leaderboard
Your score posts to a global, persistent leaderboard scored by points first, time as tiebreaker.
Hedgehog signaling in 60 seconds
Hedgehog uses an inhibitor-of-an-inhibitor logic. In the absence of ligand, Patched (PTCH1) - a 12-pass TM protein - keeps Smoothened (SMO) - a 7-pass TM signal transducer - inhibited.
Sonic Hedgehog (SHH) is post-translationally modified with cholesterol and palmitate before secretion. SHH binds Patched, removes its inhibition of SMO, and SMO accumulates in the primary cilium. Active SMO inhibits the SUFU-GLI complex, releasing full-length GLI activator (GLI-A).
GLI-A enters the nucleus and activates target genes (PTCH1, GLI1, BCL2, cyclin D1, BMI1). The pathway negatively feedbacks: PTCH1 itself is a Hedgehog target gene, restoring the brake.
Pathology: PTCH1 loss -> Gorlin syndrome (basal cell nevus syndrome) with multiple BCCs, medulloblastomas, and rhabdomyosarcomas. Vismodegib + sonidegib are SMO inhibitors approved for advanced BCC. Holoprosencephaly (failed forebrain bisection) follows SHH-pathway loss-of-function or cyclopamine teratogen exposure.
FAQ
Why does Hedgehog signaling require the primary cilium?
In vertebrates, SMO must traffic to and accumulate in the primary cilium for full activation. Patched, SUFU, and GLI processing also occur in / near the cilium. Defects in primary cilium biogenesis (ciliopathies - Joubert, Meckel, oral-facial-digital syndromes) disrupt Hedgehog signaling and produce overlapping developmental syndromes. Drosophila Hedgehog does NOT require cilia, illustrating vertebrate-specific co-option.
What is the cyclopamine story?
Pregnant ewes that grazed on Veratrum californicum gave birth to lambs with cyclopia (one fused eye). The plant alkaloid cyclopamine was identified as a SMO inhibitor and inspired the development of vismodegib decades later. The link: SHH normally bisects the developing forebrain into two hemispheres; SMO inhibition disrupts the midline, causing holoprosencephaly with single-eye phenotype.
Why is PTCH1 'unusual' for a receptor?
Patched has 12 transmembrane passes - the architecture of a transporter (RND family), not a typical 7TM GPCR or single-pass RTK. It also INHIBITS its downstream effector (SMO) in the absence of ligand, which is unusual. The 'transporter-like' structure may pump cholesterol or oxysterols away from SMO, biochemically inhibiting it. Hedgehog binding releases this transport-like inhibition.
Do I need an account to play?
No. The tournament is fully public. You get a randomized handle and your score posts to the public leaderboard at the bottom of this page.