Abstracts - Society for Developmental Biology

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Program/Abstract # 4
RA-FGF antagonism during vertebrate body axis extension: feedback signaling from stem cell progeny to niche
Duester, Gregg L.; Cunningham, Thomas; Brade, Thomas, Sanford-Burnham, La Jolla, United States; Trainor, Paul,
Stowers, Kansas City, United States; Sandell, Lisa (University of Louisville, United States)
Vertebrate embryos develop in a head to tail fashion from a caudal progenitor zone. During body axis extension,
bipotential neuromesodermal stem cells in the caudal progenitor zone generate progeny that contribute to both
neuroectoderm (hindbrain-spinal cord) and paraxial mesoderm (somites). Presomitic mesoderm exits the caudal progenitor
zone and undergoes segmentation into somites anterior to a wavefront of Fgf8 activity generated in caudal progenitors. A
major transition in mouse development occurs at E7.5 when presomitic mesoderm begins generating retinoic acid (RA) via
Rdh10 and Raldh2 enzymes that sequentially metabolize retinol to retinaldehyde and then to RA which acts as a diffusible
signal. Embryos deficient in RA synthesis exhibit small somites and limb defects that we have hypothesized are the result
of expanded Fgf8 expression, but it is unclear how RA regulates mesoderm development. Here, we show that reduction of
FGF signaling in Raldh2-/- embryos lacking RA synthesis is sufficient to rescue somitogenesis. Rdh10 mutants initially
lack RA synthesis and exhibit expanded Fgf8 expression and small somites as well as stunted forelimbs, but later recover
normal caudal somites and hind limbs due to late-appearing RA activity that arises at the neuroectoderm/epiblast junction;
a RA-reporter transgene sensitive to 0.25 nM RA demonstrates that RA activity does not act in presomitic mesoderm for
somitogenesis and that RA is not required for limb patterning. Our findings demonstrate that progeny of the caudal
progenitor zone produce RA that controls axial development by feedback signaling to the border of the stem cell niche
designed to repress Fgf8 in neuromesodermal stem cells at the neuroectoderm/epiblast junction.
Program/Abstract # 5
Muscle satellite cells are primed for myogenesis, but maintain quiescence with sequestration of Myf5 mRNA
targeted by microRNA-31 in mRNP granules
Crist, Colin G., McGill University, Montreal, Canada; Montarras, Didier; Buckingham, Margaret (Institut Pasteur, Paris,
France)
Regeneration of adult tissues depends on stem cells that are primed to enter a differentiation programme, while remaining
quiescent. How these two characteristics can be reconciled is exemplified by skeletal muscle where the majority of
quiescent satellite cells transcribe the myogenic determination gene Myf5, without activating the myogenic programme. We
show that Myf5 mRNA, together with microRNA-31, which regulates its translation, are sequestered in mRNP granules
present in the quiescent satellite cell. In activated satellite cells, mRNP granules are dissociated, relative levels of miR-31
are reduced, and Myf5 protein accumulates, which initially requires translation, but not transcription. Conditions that
promote the continued presence of mRNP granules delay the onset of myogenesis. Manipulation of miR-31 levels affects
satellite cell differentiation ex vivo and muscle regeneration in vivo. We therefore propose a model in which posttranscriptional
mechanisms hold quiescent stem cells poised to enter a tissue specific differentiation programme.
Program/Abstract # 6
Predominant role of Hoxa5 gene during mouse lung development
Jeannotte, Lucie; Boucherat, Olivier; Montaron, Séverine; Aubin, Josée (University of Laval, Canada); Philippidou,
Polyxeni; Dasen, Jeremy (NYU School of Medicine, United States)
Lung development depends on reciprocal interactions between the epithelium and the surrounding mesenchyme. The
mesenchyme can instruct epithelial differentiation but the nature of the mesenchymal factors involved still remains elusive.
Hox genes encode transcription factors specifying regional identity along the body axes and in regulating morphogenesis
during development. In mammals, 39 Hox genes are organized in 4 clusters and classified in 13 paralog groups. Several
Hox genes are expressed in a distinct spatio-temporal fashion during lung ontogeny and their expressionis mainly restricted
to lung mesenchyme. Except for Hoxa5, the lack of overt lung phenotype in single mutants suggests that, taken
individually, these Hox genes do not play a predominant role in lung ontogeny. Functional redundancy may also mask
anomalies. Most Hoxa5-/- mice die at birth from respiratory distress due to tracheal and lung dysmorphogenesis, whereas
mutations of the other paralog members Hoxb5 and Hoxc5 do not cause phenotypes that impact on life. The severity of the
Hoxa5 lung phenotype indicates a major role for Hoxa5 in lung formation. We have produced Hoxa5;Hoxb5 compound
mutants to evaluate the relative importance of these two paralogs in lung development. Hoxa5 gene plays an exclusive role
in the specification of epithelial type 1 alveolar cells, in trachea formation and in diaphragm innervation. Branching of the
bronchial tree and goblet cell specification involve both Hoxa5 and Hoxb5 genes. Thus, Hoxa5 and Hoxb5 genes share
some functions during lung ontogeny, but Hoxa5 appears to play a predominant role. (Supported by a CIHR grant)