The Maternal Maverick/GDF15-like TGF-? Ligand Panda Directs Dorsal-Ventral Axis
Formation by Restricting Nodal Expression in the Sea Urchin Embryo
#MMPMID26352141
Haillot E
; Molina MD
; Lapraz F
; Lepage T
PLoS Biol
2015[]; 13
(9
): e1002247
PMID26352141
show ga
Specification of the dorsal-ventral axis in the highly regulative sea urchin
embryo critically relies on the zygotic expression of nodal, but whether maternal
factors provide the initial spatial cue to orient this axis is not known.
Although redox gradients have been proposed to entrain the dorsal-ventral axis by
acting upstream of nodal, manipulating the activity of redox gradients only has
modest consequences, suggesting that other factors are responsible for orienting
nodal expression and defining the dorsal-ventral axis. Here we uncover the
function of Panda, a maternally provided transforming growth factor beta (TGF-?)
ligand that requires the activin receptor-like kinases (Alk) Alk3/6 and Alk1/2
receptors to break the radial symmetry of the embryo and orient the
dorsal-ventral axis by restricting nodal expression. We found that the double
inhibition of the bone morphogenetic protein (BMP) type I receptors Alk3/6 and
Alk1/2 causes a phenotype dramatically more severe than the BMP2/4
loss-of-function phenotype, leading to extreme ventralization of the embryo
through massive ectopic expression of nodal, suggesting that an unidentified
signal acting through BMP type I receptors cooperates with BMP2/4 to restrict
nodal expression. We identified this ligand as the product of maternal Panda
mRNA. Double inactivation of panda and bmp2/4 led to extreme ventralization,
mimicking the phenotype caused by inactivation of the two BMP receptors.
Inhibition of maternal panda mRNA translation disrupted the early spatial
restriction of nodal, leading to persistent massive ectopic expression of nodal
on the dorsal side despite the presence of Lefty. Phylogenetic analysis indicates
that Panda is not a prototypical BMP ligand but a member of a subfamily of TGF-?
distantly related to Inhibins, Lefty, and TGF-? that includes Maverick from
Drosophila and GDF15 from vertebrates. Indeed, overexpression of Panda does not
appear to directly or strongly activate phosphoSmad1/5/8 signaling, suggesting
that although this TGF-? may require Alk1/2 and/or Alk3/6 to antagonize nodal
expression, it may do so by sequestering a factor essential for Nodal signaling,
by activating a non-Smad pathway downstream of the type I receptors, or by
activating extremely low levels of pSmad1/5/8. We provide evidence that, although
panda mRNA is broadly distributed in the early embryo, local expression of panda
mRNA efficiently orients the dorsal-ventral axis and that Panda activity is
required locally in the early embryo to specify this axis. Taken together, these
findings demonstrate that maternal panda mRNA is both necessary and sufficient to
orient the dorsal-ventral axis. These results therefore provide evidence that in
the highly regulative sea urchin embryo, the activity of spatially restricted
maternal factors regulates patterning along the dorsal-ventral axis.
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