LMP4 regulates Tbx5 protein subcellular localization and activity.
The limb- and heart-specific Tbx5 transcription factor coexpresses with and directly binds to the novel PDZ-LIM domain protein, LMP4. LMP4 is distributed in the cytoplasm associated with the actin cytoskeleton. In the presence of LMP4, Tbx5 shuttles dynamically between the nucleus and cytoplasm and, in a complex with LMP4, localizes to actin filaments. Nuclear and cytoplasmic Tbx5 distribution in developing chicken wings suggests the functional significance of the LMP4-Tbx5 interaction. In primary epicardial cells, we demonstrate that Tbx5 protein subcellular relocalization can be stimulated by external signals that induce cell differentiation. To test whether the relocalization from nuclear to cytoplasmic sites interferes with downstream gene expression, we used limb-specific Fgf10 and heart-specific Anf promoter-luciferase reporters and demonstrate that LMP4 acts as a repressor of Tbx5 activity. These studies reveal a previously unknown mechanism for Tbx transcription factor regulation in vertebrate limb and heart development and provide a better understanding of the molecular basis of hand/heart birth defects associated with Tbx5 mutations.
Camarata
Troy
T
Department of Pediatrics, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614, USA.
Bimber
Benjamin
B
Kulisz
Andre
A
Chew
Teng-Leong
TL
Yeung
Jennifer
J
Simon
Hans-Georg
HG
D000199:Actins / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D019556:COS Cells; D002451:Cell Compartmentation; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D010496:Pericardium / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D014921:Wings, Animal / Q000166:cytology
D000199:Actins; D051526:Fibroblast Growth Factor 10; D011506:Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D009320:Atrial Natriuretic Factor