Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum.
The generation and maintenance of a plethora of neuronal subtypes is essential for normal brain function. Nevertheless, little is known about the molecular mechanisms that maintain the defining characteristics of neurons following their initial postmitotic specification. Using conditional gene ablation in mice, we demonstrate here that the homeodomain protein LIM homeobox (Lhx)7 is essential for maintaining the morphological and molecular characteristics of cholinergic interneurons of the striatum. Lhx7-depleted cholinergic interneurons extinguish expression of several subtype-specific markers, including choline acetyl transferase and Isl1, and are respecified into Lhx6-expressing mature GABAergic interneurons. Additional expression studies support a model where Lhx7 controls the choice between cholinergic or GABAergic identity by gating a cross inhibitory regulation between Isl1 and Lhx6. By demonstrating that the switch between alternative striatal interneuron fates depends on persistent activity of a single transcription factor, we provide evidence that the intrinsic plasticity of mammalian forebrain neuronal subtypes is maintained after the initial specification and lineage commitment and possibly throughout life.
Division of Molecular Neurobiology, Medical Research Council, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
Rita
R
Lopes
Nicole
N
Verhey van Wijk
Guilherme
G
Neves
Vassilis
V
Pachnis
D000818:Animals; D002454:Cell Differentiation; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000166:cytology / Q000378:metabolism*; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D007395:Interneurons / Q000166:cytology* / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D008938:Mitosis; D008954:Models, Biological; D017072:Neostriatum / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
C112960:LIM homeobox protein 8; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D002795:Choline O-Acetyltransferase; C045073:Cre recombinase; D019426:Integrases