axises

• The Anterior-Posterior Axis is controlled by the activity of the Zone of Polarizing Activity (ZPA), a specialized region in the limb bud.
• The ZPA secretes signaling molecules that form a gradient along the anterior-posterior axis.
• Classic experiments involved grafting ZPA tissue from one limb bud to another, resulting in duplication of digit patterns.
• The use of genetic knockout mice confirmed the role of specific genes in ZPA, such as Sonic Hedgehog (Shh), in anterior-posterior patterning.
• Hedgehog Signaling involves Sonic Hedgehog (Shh), Patched (Ptch), and Smoothened (Smo).
• Sonic Hedgehog (Shh) is secreted by ZPA, forming a concentration gradient.
• Patched (Ptch) is the receptor for Sonic Hedgehog (Shh).
• Smoothened (Smo) is activated upon binding of Sonic Hedgehog (Shh) to Ptch.
• Gli transcription factors mediate Sonic Hedgehog (Shh) signaling effects.
• Dorso-Ventral Axis: Mechanism: BMP (Bone Morphogenetic Protein) signaling gradient controls dorsal-ventral patterning.
• High BMP levels dorsalize tissue, while low levels ventralize.
• Experimental Evidence: Ectopic application of BMP proteins led to dorsalization of limb tissue in chick embryos.
• Inhibition of BMP signaling resulted in ventralization of limb tissue.
• Key Signaling Pathway: BMP Signaling.
• Key Molecules: BMP ligands: Bind to BMP receptors.
• BMP receptors (BMPR): Include type I (e.g., BMPR1A) and type II (e.g., BMPR2).
• Smad transcription factors: Transmit signals from BMP receptors to the nucleus.
• Chordin and Noggin: BMP inhibitors that regulate BMP signaling.
• Proximo-Distal Axis: Mechanism: FGF (Fibroblast Growth Factor) signaling plays a crucial role in limb outgrowth along the proximo-distal axis.
• FGFs secreted from the apical ectodermal ridge (AER) stimulate limb bud outgrowth.
• Removal or inhibition of the AER led to arrested limb development.
• Application of FGF proteins rescued limb outgrowth in experimental models.
• FGF Signaling: Key Molecules: Fibroblast Growth Factors (FGFs): Released by AER cells.
• Fibroblast Growth Factor Receptors (FGFRs): Include tyrosine kinase receptors.
• Downstream signaling molecules: Include MAPK and PI3K pathways.
• Partners: Engrailed-1 (En1): Regulates Fgf4 expression in the AER.
• Shh acts as a morphogen, forming a gradient in the limb bud.
• Binding of Shh to Ptch relieves inhibition on Smo, activating downstream signaling.
• Gli transcription factors mediate Shh effects, influencing target gene expression.
• Sonic Hedgehog (Shh) is produced by ZPA cells and induces digit formation in a concentration-dependent manner.
• Patched (Ptch) is the receptor for Shh and inhibits Smo in the absence of Shh.
• Smoothened (Smo) is activated upon binding of Shh to Ptch and initiates downstream signaling events.
• Gli1, Gli2, and Gli3 are Gli transcription factors that control target gene expression in response to Shh signaling.
• ZPA Grafting involves the transplantation of ZPA tissue to different locations which induces duplication of digit patterns, demonstrating the role of Shh in specifying anterior-posterior limb identity.
• Genetic Knockout Mice lacking Shh or downstream components exhibit limb abnormalities, providing evidence for the essential role of Shh signaling in limb development.