An Hh-Dependent Pathway in Lateral Plate Mesoderm Enables the Generation of Left/Right Asymmetry

Abstract

Summary Breaking bilateral symmetry is critical for the morphogenesis and placement of vertebrate organ systems. The first overt evidence of L-R asymmetry in the mouse is a rightward looping of the heart tube at early somite stages (ss) (~E8.5). Shortly thereafter, the embryo rotates 180° internalizing the gut [1, 2]. Molecular asymmetries begin earlier, with the expression of the TGFβ family member Nodal in the left lateral plate mesoderm (LPM) [3–5]. Nodal induces left LPM expression of Pitx2, a critical determinant of left sided identity, and Lefty-2, a related TGFβ family member [6–8] which antagonizes Nodal signaling [9]. Nodal signaling is confined to the left LPM through that antagonistic action of Lefty-1 secreted by cells in the left half of the prospective floor plate (PFP) [10]. The asymmetric expression of Nodal is linked to left-orientated, cilia-generated flow within a midline structure, the ventral node [11, 12]. Directional symmetry breaking is superimposed on a poorly understood Hedgehog (Hh) signaling-based mechanism that enables the establishment of L-R asymmetry. Mouse embryos lacking both Sonic hedgehog (Shh) and Indian hedgehog (Ihh), or Smoothened (Smo), an obligate membrane component in the transduction of all Hh signals, fail to activate Nodal in the LPM or Lefty-1 in the PFP, their heart remains as a linear tube and embryos die of circulatory failure shortly after E8.5 [13]. These results, together with reports of directional trafficking of Shh within membranous, nodal vesicular parcels (NVPs), have lead to a model wherein Hh signaling in the node indirectly enables the establishment of molecular asymmetry in LPM of the mammalian embryo [14]. Here, we provide evidence for a direct action of mouse Hh signaling in LPM. Further, we identify a downstream pathway that establishes a competence for Nodal activation in LPM, and as a consequence, the generation of L-R asymmetry.

Notch and Nodal control forkhead factor expression in the specification of multipotent progenitors in sea urchin

“…Nevertheless, how the two signaling systems relate to each other mechanistically remains unknown. Laterality defects in mice caused by loss of Hh signaling can be rescued by expression of a constitutively active Smo receptor in lateral plate mesoderm resulting in unilateral expression of nodal (Tsiairis and McMahon, 2009). In sea urchins, overexpression of a constitutively active Smo receptor randomizes the position of the adult rudiment (Walton et al, 2009).…”

“…Hh signaling triggers coelomic pouch morphogenesis Hh signaling is known to regulate developmental processes as diverse as patterning, proliferation and morphogenesis (Ingham and McMahon, 2001) and has been linked to the establishment of L/R asymmetry (Tsiairis and McMahon, 2009). In sea urchin embryos the Hh ligand is expressed throughout the endoderm and archenteron starting at the mesenchyme blastula stage (Fig.…”

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…all converge on asymmetric Nodal expression during much later development? For example, Sonic hedgehog is a crucial early asymmetric gene in the chick node (Levin et al, 1995), but is not necessary in mouse node for normal asymmetry (Tsiairis and McMahon, 2009 heterotaxia (randomization and independent sidedness of each organ) in LR phenotypes, we still have very little understanding of the mechanisms underlying concordance among organs in wild-type or situs inversus individuals, or the differences underlying heterotaxia, situs inversus, and isomerisms (which, oddly, are never seen in Xenopus).…”

Rab23 regulates Nodal signaling in vertebrate left–right patterning independently of the Hedgehog pathway

“…Smo mutant embryos lack all Hh signaling and fail to express Nodal in the LPM. The absence of Nodal expression in Smo mutants appears to be caused by defective Foxf1/Bmp4 expression in the LPM and reduction of Gdf1 and Cryptic in the node (Zhang et al, 2001;Tsiairis and McMahon, 2009). Ptch1 mutants, on the other hand, have dramatically elevated levels of Hh signaling, yet they exhibit normal Nodal expression in the left LPM, indicating that Hh signaling has a permissive role in allowing Nodal expression in the mouse.…”