PITX2 gain-of-function induced defects in mouse forelimb development.
BACKGROUND
Limb development and patterning originate from a complex interplay between the skeletal elements, tendons, and muscles of the limb. One of the genes involved in patterning of limb muscles is the homeobox transcription factor Pitx2 but its role in forelimb development is uncharacterized. Pitx2 is expressed in the majority of premature presumptive forelimb musculature at embryonic day 12.5 and then maintained throughout embryogenesis to adult skeletal muscle.


RESULTS
To further study the role of Pitx2 in forelimb development we have generated transgenic mice that exhibit a pulse of PITX2 over-expression at embryonic day 13.5 and 14.5 in the developing forelimb mesenchyme. These mice exhibit a distal misplacement of the biceps brachii insertion during embryogenesis, which twists the forelimb musculature resulting in severe skeletal malformations. The skeletal malformations have some similarities to the forearm deformities present in Leri-Weill dyschondrosteosis.


CONCLUSIONS
Taken together, the tendon, muscle, and bone anomalies further support a role of Pitx2 in forelimb development and may also shed light on the interaction between the skeletal elements and muscles of the limb during embryogenesis.
Holmberg
Johan
J
Department of Experimental Medical Science, Division for Cell and Matrix Biology, Lund University, Lund, Sweden. johan_k.holmberg@med.lu.se
Ingner
Gorel
G
Johansson
Curt
C
Leander
Peter
P
Hjalt
Tord A
TA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities; D005552:Forelimb / Q000002:abnormalities* / Q000196:embryology* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006811:Humerus / Q000002:abnormalities; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011884:Radius / Q000002:abnormalities; D013710:Tendons / Q000002:abnormalities; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014457:Ulna / Q000002:abnormalities; D000097577:Homeobox Protein PITX2
D056742:Cyclin D2; D016213:Cyclins; D018398:Homeodomain Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C486196:Ccnd2 protein, mouse; C099280:Kera protein, mouse; C497420:Six2 protein, mouse