A chemical-genetic approach to studying neurotrophin signaling.

Abstract:

:Trk tyrosine kinases are receptors for members of the neurotrophin family and are crucial for growth and survival of specific populations of neurons. Yet, the functions of neurotrophin-Trk signaling in postnatal development as well as maintenance and plasticity of the adult nervous system are less clear. We report here the generation of mice harboring Trk knockin alleles that allow for pharmacological control of Trk kinase activity. Nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkA(F592A) and TrkB(F616A) neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkA(F592A), TrkB(F616A), and TrkC(F167A) signaling in vivo. Thus, Trk knockin mice provide valuable tools for selective, rapid, and reversible inhibition of neurotrophin signaling in vitro and in vivo.

journal_name

Neuron

journal_title

Neuron

authors

Chen X,Ye H,Kuruvilla R,Ramanan N,Scangos KW,Zhang C,Johnson NM,England PM,Shokat KM,Ginty DD

doi

10.1016/j.neuron.2005.03.009

subject

Has Abstract

pub_date

2005-04-07 00:00:00

pages

13-21

issue

1

eissn

0896-6273

issn

1097-4199

pii

S0896-6273(05)00204-7

journal_volume

46

pub_type

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