Highlights in DD


  • Julie C. Kiefer

“Highlights” calls attention to exciting advances in developmental biology that have recently been reported in Developmental Dynamics. Development is a broad field encompassing many important areas. To reflect this fact, the section spotlights significant discoveries that occur across the entire spectrum of developmental events and problems: from new experimental approaches, to novel interpretations of results, to noteworthy findings utilizing different developmental organisms.

Cord progression (Three-dimensional visualization of testis cord morphogenesis, a novel tubulogenic mechanism in development by Alexander N. Combes, Emmanuelle Lesieur, Vincent R. Harley, Andrew H. Sinclair, Melissa H. Little, Dagmar Wilhelm, and Peter Koopman, Dev Dyn 238:1033–1041; and Morphometric analysis of testis cord formation in Sox9-EGFP mice by Liesl Nel-Themaat, Tegy J. Vadakkan, Ying Wang, Mary E. Dickinson, Haruhiko Akiyama, and Richard R. Behringer, Dev Dyn238:1100–1110) Just as a symphony is a collection of smaller movements, so is creation of an embryonic organ. Two separate studies document testis cord morphogenesis, with Behringer's group emphasizing morphometric analysis starting from the very moments when XX and XY gonads adopt differentiating characteristics, and Koopman's group focusing on tissue remodeling during nascent to definitive cord formation. Clusters of pre-Sertoli and germ cells give rise to testis cords that form aligned, parallel loops that span the width of the gonad. Both groups use confocal analysis of fluorescently labeled cells and three-dimensional modeling to gain new insights into morphogenesis of the developing organ. Their work shows that the developmental process is surprisingly dynamic and unpredictable. Nascent cords vary in shape and size and appear perforated and interconnected. As the testis matures, the network resolves into definitive cords that still have structural variability. Not only do the number of cords differ between gonads, but also individual cords form apparently random branching and fusion events with adjacent cords. Yet the cords are regular in that they are aligned, and of consistent diameter. Testis cord formation appears to be a novel form of tubulogenesis where apparently haphazard, constant tissue remodeling resolves into a relatively orderly, mature organ. The symphony begins like a jumbled John Cage “chance music” composition, and ends like a structured, classical work by J.S. Bach.

Herding Hedgehog (Tulp3 is a critical repressor of mouse hedgehog signaling by Don A. Cameron, Tracie Pennimpede, and Martin Petkovich, Dev Dyn238:1140–1149) Managing Sonic hedgehog (Shh) activity is a bit like herding cats, it takes an unrelenting, synchronized effort. Shh is a potent developmental regulator that specifies fates of ventral neural tube (nt) cells and patterns the limb in a concentration-dependent manner. Pathway activation is held in check by modification of a downstream effector, Gli3, which is processed to form a repressor, Gli3R, in the absence of the Shh ligand. Here, Cameron et al., show that Tubby-like protein 3 (Tulp3) reinforces Gli3R by working as a repressor of Shh pathway activity. Tulp3−/− phenotypes show signs of increased Shh signaling, including dorsal expansion of ventral nt neural progenitor domains and anterior expansion of posterior limb bud markers. Tulp3−/−, Shh−/− double mutants have Tulp3−/− like phenotypes, showing that Tulp3 is epistatic to Shh. Evidence suggests, however, that Tulp3 does not simply antagonize Shh. Downstream Shh targets are expressed in the absence of the ligand in Tulp3/Shh compound mutants. Tulp3, then, likely plays a role in shutting off the Shh signal transduction pathway when the Shh ligand is not present. Another surprising finding is that in Tulp3−/− limbs, which exhibit polydactyly, Pax9 expression disappears, but Gli3 remains unchanged. This shows that altered Shh target gene expression could result from impaired Gli3 processing to Gli3R. The work goes to show that there's more than one way to skin a cat—or hedgehog.

Illuminating ill-effects (Increased Hox activity mimics the teratogenic effects of excess retinoic acid signaling by Joshua S. Waxman and Deborah Yelon, Dev Dyn238:1207–1213) In the 1980s, approximately 1,000 malformed children and over 6,000 abortions (spontaneous and elective) were the tragic consequence of pregnant women who used the retinoic acid (RA)-based drug Accutane. Teratogenic affects of retinoic acid are widespread but include heart patterning defects, of which underlying mechanisms are not well understood. Waxman and Yelon show that overexpression of hoxb5b, a likely direct target of RA signaling, mimics many of the heart phenotypes of zebrafish treated with ectopic RA. Ectopic application of both agents can cause small ventricles while atria are of normal size. The morphological phenotype is reflected by reduced numbers of ventricle cells and ventricular myosin heavy chain (mhc) expression while those of atrial cells and atrial mhc are nearly unchanged. These observations show that both Hoxb5b and RA differentially affect ventricular and atrial cells, and debunk the theory that RA causes ventricular precursors to adopt atrial fate. Differences between hoxb5b and RA effects were also noted. Among them, hoxb5b overexpression never resulted in increased number of atrial cells or in a high percentage of animals without hearts, as can specific concentrations of RA. One possible explanation is that additional downstream hox genes cause the dissimilar phenotypes. Terrible mistakes of the past light the way to the future. It remains to be seen whether endogenous RA signaling also differentially regulates atrial and ventricular lineages.