#left-right asymmetry

Morphogen Induction-l

Which morphogen plays a key role in left-right axis determination?

Left-right asymmetry originates near embryonic node where motile cilia generate leftward fluid flow concentrating Nodal around left lateral plate mesoderm. Nodal, TGF-beta member, activates left-specific cascade including Pitx2 specifying left identity of heart looping and gut situs. Nodal antagonists Lefty2 and Cerberus restrict signal to left, while BMP and FGF modulate intensity. Mutations in Nodal or ciliary dynein cause situs inversus. Fibronectin matrix, Sox2 pluripotency factor and actin cytoskeleton lack instructive laterality information. Nodal gradient thus acts as critical left-right determinant linking ciliary flow to organ laterality and visceral patterning.

Ref: Shiratori and Hamada, Development 2006, Nodal and Left-Right Axis Determination.

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Paracrine Factor

Which signaling pathway primarily regulates left-right asymmetry in vertebrate embryos?

Left-right asymmetry initiation involves ciliary flow-driven Nodal asymmetry conserved vertebrates from mouse to human. Motile monocilia at embryonic node generate leftward fluid flow concentrating Nodal vesicles containing Sonic hedgehog and retinoic acid. Nodal, TGF-beta family ligand, expressed left lateral plate mesoderm signaling via ALK4/7 ActRIIB receptors activating Smad2/3 and FoxH1 transcription factor inducing Pitx2 homeobox controlling organ situs dextra versus sinistra, heart looping direction. Right side antagonists Lefty1/2 and Cerl2 restrict spread via feedback. Hedgehog provides upstream node patterning but Nodal-Pitx2 cascade definitive executor. Mutations cause heterotaxy, situs inversus syndromes linking morphogen asymmetry.

Ref: Levin, Genes & Development 2005: Nodal-Pitx2 pathway establishes vertebrate left-right asymmetry downstream of ciliary flow.

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Elegans -ll

Which pathway regulates left-right asymmetry in C. elegans?

Left-right asymmetry in C. elegans morphogenesis involves Nodal-related signaling despite absence of classical Nodal in worms. Recent work identifies UNC-6/Netrin and TGFbeta family member TIG-3 related to Activin/Nodal acting through SMA-6 and DAF-4 receptors regulating asymmetric positioning of gut, gonad and AB lineage divisions such as ABar spindle skewing. While early cleavage asymmetry uses Notch and Wnt, later organ laterality requires this Activin-like cascade. Although vertebrates use Nodal-Lefty-Pitx2, conserved type I and II TGFbeta pathway components were shown to influence nematode left-right handedness of blastomere divisions and gut rotation, classified as Nodal/Activin related signaling module.

Ref: WormBook Embryogenesis: Nodal/Activin-related pathway regulates left-right asymmetry in C. elegans embryogenesis.

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chick development-l

Cerberus protein on the left side of chick embryos activates:

At stage when left-right asymmetry established, Sonic hedgehog expressed left of Hensen's node induces Cerberus-related Caronte in left paraxial and lateral plate mesoderm. Caronte functions as high-affinity BMP antagonist binding BMP2, BMP4, BMP7 extracellularly, preventing Smad1/5/8 phosphorylation that normally represses Nodal promoter via interplay with FoxH1 and Smad2. BMP inhibition lifts repression permitting Nodal autoactivation left side, followed by Lefty and Pitx2 expression directing asymmetric organ morphogenesis. Right side lacking Caronte maintains BMP blocking Nodal, explaining indirect Nodal activation by Cerberus.

Ref: Gilbert, Developmental Biology, 12th ed., Chapter 12: Cerberus activates Nodal via BMP inhibition in left-right patterning.

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