Islet-to-LMO stoichiometries control the function of transcription complexes that specify motor neuron and V2a interneuron identity.
LIM transcription factors bind to nuclear LIM interactor (Ldb/NLI/Clim) in specific ratios to form higher-order complexes that regulate gene expression. Here we examined how the dosage of LIM homeodomain proteins Isl1 and Isl2 and LIM-only protein Lmo4 influences the assembly and function of complexes involved in the generation of spinal motor neurons (MNs) and V2a interneurons (INs). Reducing the levels of Islet proteins using a graded series of mutations favored V2a IN differentiation at the expense of MN formation. Although LIM-only proteins (LMOs) are predicted to antagonize the function of Islet proteins, we found that the presence or absence of Lmo4 had little influence on MN or V2a IN specification. We did find, however, that the loss of MNs resulting from reduced Islet levels was rescued by eliminating Lmo4, unmasking a functional interaction between these proteins. Our findings demonstrate that MN and V2a IN fates are specified by distinct complexes that are sensitive to the relative stoichiometries of the constituent factors and we present a model to explain how LIM domain proteins modulate these complexes and, thereby, this binary-cell-fate decision.
Song
Mi-Ryoung
MR
Bioimaging Research Center and Cell Dynamics Research Center, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea. msong@gist.ac.kr
Sun
Yunfu
Y
Bryson
Ami
A
Gill
Gordon N
GN
Evans
Sylvia M
SM
Pfaff
Samuel L
SL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007395:Interneurons / Q000166:cytology / Q000378:metabolism*; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; C558561:Isl2 protein, mouse; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; C491976:Lmo4 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1