Tbx1 and Brn4 regulate retinoic acid metabolic genes during cochlear morphogenesis.
BACKGROUND
In vertebrates, the inner ear is comprised of the cochlea and vestibular system, which develop from the otic vesicle. This process is regulated via inductive interactions from surrounding tissues. Tbx1, the gene responsible for velo-cardio-facial syndrome/DiGeorge syndrome in humans, is required for ear development in mice. Tbx1 is expressed in the otic epithelium and adjacent periotic mesenchyme (POM), and both of these domains are required for inner ear formation. To study the function of Tbx1 in the POM, we have conditionally inactivated Tbx1 in the mesoderm while keeping expression in the otic vesicle intact.


RESULTS
Conditional mutants (TCre-KO) displayed malformed inner ears, including a hypoplastic otic vesicle and a severely shortened cochlear duct, indicating that Tbx1 expression in the POM is necessary for proper inner ear formation. Expression of the mesenchyme marker Brn4 was also lost in the TCre-KO. Brn4-;Tbx1+/-embryos displayed defects in growth of the distal cochlea. To identify a potential signal from the POM to the otic epithelium, expression of retinoic acid (RA) catabolizing genes was examined in both mutants. Cyp26a1 expression was altered in the TCre-KO, while Cyp26c1 showed reduced expression in both TCre-KO and Brn4-;Tbx1+/- embryos.


CONCLUSIONS
These results indicate that Tbx1 expression in the POM regulates cochlear outgrowth potentially via control of local retinoic acid activity.
Braunstein
Evan M
EM
Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. ebraunst@aecom.yu.edu
Monks
Dennis C
DC
Aggarwal
Vimla S
VS
Arnold
Jelena S
JS
Morrow
Bernice E
BE
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D003051:Cochlea / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D007758:Ear, Inner / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000378:metabolism; D009024:Morphogenesis / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D050809:POU Domain Factors / Q000235:genetics* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; C074067:Pou3f4 protein, mouse; D014212:Tretinoin