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PITX2 gain-of-function induced defects in mouse forelimb development.

Holmberg J, Ingner G, Johansson C, Leander P, Hjalt TA - BMC Dev. Biol. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medical Science, Division for Cell and Matrix Biology, Lund University, Lund, Sweden. johan_k.holmberg@med.lu.se

ABSTRACT

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.

Conclusion: 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.

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Related in: MedlinePlus

Forelimbs of adult Ktcn-PITX2 mice display tendon anomalies. (A and B) The adult Ktcn-PITX2 limb musculature is twisted 180 degrees compared to wild type. Still, all muscle groups are present. (C) Normally, biceps brachii inserts at the proximal part of the radius (white arrow). (D) In the Ktcn-PITX2 mice biceps brachii insertion is altered (white arrow) as its distal end is curled around the radius (black arrow) and inserts dorsally at the very most distal part of the bone.
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Figure 7: Forelimbs of adult Ktcn-PITX2 mice display tendon anomalies. (A and B) The adult Ktcn-PITX2 limb musculature is twisted 180 degrees compared to wild type. Still, all muscle groups are present. (C) Normally, biceps brachii inserts at the proximal part of the radius (white arrow). (D) In the Ktcn-PITX2 mice biceps brachii insertion is altered (white arrow) as its distal end is curled around the radius (black arrow) and inserts dorsally at the very most distal part of the bone.

Mentions: To gain a deeper understanding of the forelimb phenotype we dissected forelimbs from adult Ktcn-PITX2 mice. Despite the obvious twist of the musculature, all muscle groups are present and originate and insert correctly except for biceps brachii. Biceps brachii is a flexor muscle whose function is to decrease the joint angle at the elbow but also to supinate (turn palm superiorly or anteriorly) the forearm at the radioulnar joints. It originates at two separate sites in the scapula and inserts at the proximal part of the radius. In the Ktcn-PITX2 mice biceps brachii insertion is altered as its distal tendon is curled around the radius and inserts dorsally at the very most distal part of the bone (Figure 7). This would explain the limited elbow motion but also the permanent pronation of the Ktcn-PITX2 forelimbs. Muscle groups work as antagonists. If the supination movement is impaired its antagonist, the pronator, will dominate, which may result in the pronation position.


PITX2 gain-of-function induced defects in mouse forelimb development.

Holmberg J, Ingner G, Johansson C, Leander P, Hjalt TA - BMC Dev. Biol. (2008)

Forelimbs of adult Ktcn-PITX2 mice display tendon anomalies. (A and B) The adult Ktcn-PITX2 limb musculature is twisted 180 degrees compared to wild type. Still, all muscle groups are present. (C) Normally, biceps brachii inserts at the proximal part of the radius (white arrow). (D) In the Ktcn-PITX2 mice biceps brachii insertion is altered (white arrow) as its distal end is curled around the radius (black arrow) and inserts dorsally at the very most distal part of the bone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2275225&req=5

Figure 7: Forelimbs of adult Ktcn-PITX2 mice display tendon anomalies. (A and B) The adult Ktcn-PITX2 limb musculature is twisted 180 degrees compared to wild type. Still, all muscle groups are present. (C) Normally, biceps brachii inserts at the proximal part of the radius (white arrow). (D) In the Ktcn-PITX2 mice biceps brachii insertion is altered (white arrow) as its distal end is curled around the radius (black arrow) and inserts dorsally at the very most distal part of the bone.
Mentions: To gain a deeper understanding of the forelimb phenotype we dissected forelimbs from adult Ktcn-PITX2 mice. Despite the obvious twist of the musculature, all muscle groups are present and originate and insert correctly except for biceps brachii. Biceps brachii is a flexor muscle whose function is to decrease the joint angle at the elbow but also to supinate (turn palm superiorly or anteriorly) the forearm at the radioulnar joints. It originates at two separate sites in the scapula and inserts at the proximal part of the radius. In the Ktcn-PITX2 mice biceps brachii insertion is altered as its distal tendon is curled around the radius and inserts dorsally at the very most distal part of the bone (Figure 7). This would explain the limited elbow motion but also the permanent pronation of the Ktcn-PITX2 forelimbs. Muscle groups work as antagonists. If the supination movement is impaired its antagonist, the pronator, will dominate, which may result in the pronation position.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medical Science, Division for Cell and Matrix Biology, Lund University, Lund, Sweden. johan_k.holmberg@med.lu.se

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus