Zone of Polarizing Activity Regulatory Sequence Mutations/Duplications with Preaxial Polydactyly and Longitudinal Preaxial Ray Deficiency in the Phenotype: A Review of Human Cases, Animal Models, and Insights Regarding the Pathogenesis

Figure 2

(a) Prepatterning establishes anteroposterior polarity of the early limb bud as a result of the antagonistic activity of GLI3R anteriorly and HAND2 posteriorly. This results in establishing competency for ZPA (Zone of Polarizing Activity) induction in the posterior mesoderm. (b) Next, SHH is induced within the ZPA (colored dark green) by HAND2 and 5′HOXD. (c) Following the expression of SHH, its maintenance is through WNT7A and the SHH-FGF4 feedback loop. (d) “Restriction” of SHH (preventing its transcriptional activation at the most anterior part of the mesoderm) is mediated by the “negative” regulators of SHH: GLI3R, ALX4, TWIST1, and EVT4/5. Note that other inhibitory regulatory modules exist such as the module described by Petit et al. [10].

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