Chemical Control of Trk Signaling in Mice

Value Proposition

·      Selective and reversible control: Enables specific inhibition of individual Trk receptors (TrkA, TrkB, TrkC) without affecting other cellular processes or wild-type neurons

·      Temporal precision: Allows researchers to control exactly when neurotrophin signaling is blocked through oral drug administration, enabling studies of acute vs. chronic effects

·      In vivo applicability: Overcomes major limitations of existing approaches by enabling Trk inhibition studies in living adult animals rather than just cell culture

·      Pharmacological convenience: Uses nanomolar concentrations of orally bioavailable compounds (1NMPP1, 1NaPP1) for easy administration and dosing control

·      Reversible inhibition: Unlike genetic knockouts, allows restoration of normal signaling when drug is withdrawn, enabling recovery studies

·      Adult nervous system research: Specifically addresses the knowledge gap in neurotrophin function in mature neurons, opening new research avenues in neuroplasticity and neurodegeneration

Unmet Need

Understanding neurotrophin signaling in adult nervous system function and maintenance has been severely limited by the lack of tools to selectively inhibit these pathways in mature animals. Prior to this technology, approaches relied primarily on genetic knockouts which eliminate neurotrophin signaling in development, making it impossible to distinguish developmental versus adult-specific functions, or use general kinase inhibitors that lack specificity for Trk receptors. Therefore, there is a strong need for selective, temporally-controlled inhibition tools to be developed to address the specific functions of neurotrophin signaling in the adult nervous system.

Technology Description

Researchers at Johns Hopkins have developed genetically modified mouse lines that enable pharmacological control of neurotrophin receptor signaling in vivo. The technology involves introducing specific point mutations (TrkA F592A, TrkB F616A, TrkC F167A) into the kinase domains of neurotrophin receptors that render them susceptible to inhibition while leaving wild-type receptors unaffected. When researchers administer compounds like 1NMPP1 or 1NaPP1 orally to these mice, the modified Trk receptors are selectively inhibited at nanomolar concentrations, allowing precise temporal control over neurotrophin signaling.

Stage of Development

·      These mouse strains are currently available through the Jax Laboratories online database:

o  TrkA^F592A (hypomorphic floxed F592A)- Strain #022362

o  Ntrk2^{loxP-F616A-loxP} (hypomorphic floxed F616A)- Strain #022363

o  B6.129P2(SJL)-Ntrk3^tm1Ddg/J (hypomorphic floxed F617A)- Strain #022364

Data Availability

·      n/a

Publication

Chen X, Ye H, Kuruvilla R, Ramanan N, Scangos KW, Zhang C, Johnson NM, England PM, Shokat KM, Ginty DD. A chemical-genetic approach to studying neurotrophin signaling. Neuron. 2005 Apr 7;46(1):13-21. doi: 10.1016/j.neuron.2005.03.009. PMID: 15820690.