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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 Ktcn-PITX2 mice exhibit severe bone malformations. (A) X-ray images and Alizarin Red staining of wild type (left panel) and Ktcn-PITX2 (right panel) adult forelimbs. Right panel: Alizarin Red staining of Ktcn-PITX2 forelimb (ventral view) shows a diminished and misplaced deltoid tuberosity. The humerus and radius are malformed. Note the proximal bend of the radius, which results in a posterior misplacement. (B) A Ktcn-PITX2 mouse displays the characteristic forelimb phenotype. Abbreviations: dt, deltoid tuberosity; h, humerus; r, radius; u, ulna.
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Figure 1: Forelimbs of Ktcn-PITX2 mice exhibit severe bone malformations. (A) X-ray images and Alizarin Red staining of wild type (left panel) and Ktcn-PITX2 (right panel) adult forelimbs. Right panel: Alizarin Red staining of Ktcn-PITX2 forelimb (ventral view) shows a diminished and misplaced deltoid tuberosity. The humerus and radius are malformed. Note the proximal bend of the radius, which results in a posterior misplacement. (B) A Ktcn-PITX2 mouse displays the characteristic forelimb phenotype. Abbreviations: dt, deltoid tuberosity; h, humerus; r, radius; u, ulna.

Mentions: The Ktcn-PITX2 forelimb phenotype occurs randomly on either left or right forelimb. Occasionally both forelimbs are affected (Table 1). The bone malformations consist of a shortened, thickened and malformed humerus and a diminished deltoid tuberosity. The humerus malformation is most prominent distally and partly distorts the olecranon fossa. The olecranon fossa is a dorsal depression that receives the olecranon (elbow) of the ulna when the forearm is extended. This leads to a slight dislocation of the proximal ulna. Radius is bent proximally and approaches the elbow joint from a straight angel (Figure 1A). This locks the elbow in a simultaneous pronation-extension and forces the ulna to bend upwards to reach the carpals. The limitations in elbow movement in combination with the 180 degrees twist of the paw makes the forelimb insufficient to support on (Figure 1B). Hindlimbs, in contrast, do not exhibit any phenotype. The Ktcn-PITX2 mice are fertile and have normal life span.


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 Ktcn-PITX2 mice exhibit severe bone malformations. (A) X-ray images and Alizarin Red staining of wild type (left panel) and Ktcn-PITX2 (right panel) adult forelimbs. Right panel: Alizarin Red staining of Ktcn-PITX2 forelimb (ventral view) shows a diminished and misplaced deltoid tuberosity. The humerus and radius are malformed. Note the proximal bend of the radius, which results in a posterior misplacement. (B) A Ktcn-PITX2 mouse displays the characteristic forelimb phenotype. Abbreviations: dt, deltoid tuberosity; h, humerus; r, radius; u, ulna.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Forelimbs of Ktcn-PITX2 mice exhibit severe bone malformations. (A) X-ray images and Alizarin Red staining of wild type (left panel) and Ktcn-PITX2 (right panel) adult forelimbs. Right panel: Alizarin Red staining of Ktcn-PITX2 forelimb (ventral view) shows a diminished and misplaced deltoid tuberosity. The humerus and radius are malformed. Note the proximal bend of the radius, which results in a posterior misplacement. (B) A Ktcn-PITX2 mouse displays the characteristic forelimb phenotype. Abbreviations: dt, deltoid tuberosity; h, humerus; r, radius; u, ulna.
Mentions: The Ktcn-PITX2 forelimb phenotype occurs randomly on either left or right forelimb. Occasionally both forelimbs are affected (Table 1). The bone malformations consist of a shortened, thickened and malformed humerus and a diminished deltoid tuberosity. The humerus malformation is most prominent distally and partly distorts the olecranon fossa. The olecranon fossa is a dorsal depression that receives the olecranon (elbow) of the ulna when the forearm is extended. This leads to a slight dislocation of the proximal ulna. Radius is bent proximally and approaches the elbow joint from a straight angel (Figure 1A). This locks the elbow in a simultaneous pronation-extension and forces the ulna to bend upwards to reach the carpals. The limitations in elbow movement in combination with the 180 degrees twist of the paw makes the forelimb insufficient to support on (Figure 1B). Hindlimbs, in contrast, do not exhibit any phenotype. The Ktcn-PITX2 mice are fertile and have normal life span.

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