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WIREs Dev Biol
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The two domain hypothesis of limb prepattern and its relevance to congenital limb anomalies

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Functional annotation of mutations that cause human limb anomalies is enabled by basic developmental studies. In this study, we focus on the prepatterning stage of limb development and discuss a recent model that proposes anterior and posterior domains of the early limb bud generate two halves of the future skeleton. By comparing phenotypes in humans with those in model organisms, we evaluate whether this prepatterning concept helps to annotate human disease alleles.

Do models of embryonic pattern formation explain congenital limb deficiencies? (a) Do problems with (early or progressive) PD pattern specification result in limb truncation (terminal deficiency) or loss of central elements (intercalary deficiency)? (b) Do problems with AP pattern formation result in anterior or posterior longitudinal limb deficiency (hemimelia)?
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Longitudinal deficiency. Femoral deficiency associated with an absent tibia is potentially attributable to misregulation of the anterior domain.
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Two domain hypothesis. (a) In the pre‐AER hindlimb, AP limb bud polarity is perpetuated by mutual antagonism between anterior and posterior domains that are defined by Irx3/5/Sall4/Gli3 and Hand2, respectively. (b) Anterior and posterior domains may generate proximal‐anterior and distal‐posterior skeletal elements, respectively.
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Factors that promote limb field initiation and initial AP polarity. Initial forelimb AP polarity is related to the colinear expression of Hox genes along the rostrocaudal embryo axis (Hox5‐9 paralogues). In contrast, initial hindlimb AP polarity is related to other factors expressed in the caudal region of the embryo such as Pitx1 and Islet1.
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Vertebrate Organogenesis > Musculoskeletal and Vascular
Birth Defects > Organ Anomalies

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