By Sophie Lin
CRISPR Screens Reveal Creld1 as a Sensory Regulator
Mice lacking a single protein displayed broad sensory deficits across touch, temperature, pain, and itch, according to a study published in Nature Neuroscience. Researchers at Tsinghua University discovered that the protein CRELD1 acts as a regulator of somatosensation by modulating sodium-channel activity, a mechanism that could offer a new drug target for treating pain and itch.
To identify the genes involved in sensation, a research team led by Bailong Xiao used CRISPR to disable selected genes in newborn mice. They tested 20 candidates after validating their method against genes with established sensory roles.
Behavioral Deficits and Normal Coordination
One candidate, Creld1, stood out for the breadth of its effects. Mice with the disrupted gene withdrew their paws less frequently when exposed to fine filaments or a soft brush.
Beyond simple touch, the animals responded less strongly to painful mechanical pressure and took longer to react to hot and cold surfaces. The team used a second genetic method to delete Creld1 specifically in neurons clustered beside the spinal cord to confirm the effect originated in sensory neurons.
These targeted mice displayed similar deficits, including barely scratching after injections of histamine or other itch-inducing substances. Crucially, the body weight, movement, and coordination of the mice all remained normal throughout the testing phase.
Direct Binding to Sodium Channels Controls Firing Rates
Detecting a stimulus and sending a strong electrical signal are separate jobs. Sensory neurons lacking CRELD1 still showed responses comparable to those of unmodified neurons when exposed to those stimuli.
However, generating electrical impulses requires sodium channels to allow charged sodium ions to cross the cell membrane. The research team found that the CRELD1 protein binds to several sodium channels and boosts their activity.
Without CRELD1, sodium currents weakened. The neurons needed stronger stimulation to fire and they produced fewer electrical impulses. Conversely, increasing CRELD1 production strengthened sodium currents and made mice more responsive to touch, heat, and cold.
Targeting Human Variants for Future Pain Therapeutics
The study, titled “Behavioral genomics identifies Creld1 as a cross-modal regulator of somatosensation,” suggests that the contact point between CRELD1 and sodium channels “might offer a precision target for drug development.”
However, the mouse results do not establish a treatment, and the human protein presents a complication. Testing two human versions of the protein in cultured cells revealed that one boosted a sodium channel’s activity while the other did not.
Researchers still need to determine which versions predominate in human sensory neurons and whether any future therapeutic can reduce unwanted sensations without dulling the everyday signals that help protect the body.
