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.

Birth Order Counts (Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse by Christine L. Jasoni, Robert W. Porteous, and Allan E. Herbison, Dev Dyn238:524–531) As the theory goes, birth order predicts one's destiny. While debatable for human life outcomes, Jasoni et al. report that it is a truism for neurons that secrete gonadotropin-releasing hormone (GnRH). These neurons, which regulate aspects of brain function required for fertility, are born in the olfactory placode and migrate to basal forebrain structures: (in rostral to caudal order) the medial septum (MS), preoptic area (POA), and anterior hypothalamic areas (AHA). To test the hypothesis that forebrain positioning is dependent on birth order, mouse embryos were pulsed with 5-bromo-2-deoxyuridine (BrdU) at time points within the developmental window when GnRH neurons differentiate, then raised to adulthood. Neurons positive for both BrdU and GnRH were identified as GnRH neurons that had just differentiated at the time of BrdU labeling. The experiments reveal that GnRH neurons occupy forebrain structures in a rostral to caudal manner over time. The majority of MS-occupied GnRH neurons (78%) differentiate at embryonic day (E) 9.5, while those in the POA do so at E9.5 (38%) and E10.5 (44%), and those in the AHA at E10.5 (36%) and E11.5 (48%). The findings suggest anatomical localization is a product of changing progenitor competence and/or migratory environments, and that their life's path is laid out from birth.

Gasp! Novel L-R Mutants (Mouse mutagenesis identifies novel roles for left–right patterning genes in pulmonary, craniofacial, ocular, and limb development by Alexander Ermakov, Jonathan L. Stevens, Elaine Whitehill, Joan E. Robson, Guido Pieles, Debra Brooker, Paraskevi Goggolidou, Nicola Powles-Glover, Terry Hacker, Stephen R. Young, Neil Dear, Elizabeth Hirst, Zuzanna Tymowska-Lalanne, James Briscoe, Shoumo Bhattacharya, and Dominic P. Norris, Dev Dyn238:581–594) It stands to reason that misalignment of structures within the heart could have dire consequences. With this in mind, the authors performed a three-generation (G3) screen in mice to identify new recessive mutations affecting L–R patterning that may shed light on origins of some forms of congenital heart defects (CHD). Identified mutants fell into two categories: left–right mutants (lrm), exhibiting only abnormal L–R patterning, and “gasping” (gpg) mutants with pleiotropic defects in cardiac development, neural tube closure, and anterior gut, limb, eye, and L–R patterning. Mapping data revealed that the five lrm mutants are two novel L–R loci, and three new alleles of L–R genes, Dnahc11 and Pkd2, while the six gpg mutants represent at least five novel L–R genes. A commonality among affected tissues and organs in gpg mutants is that they are patterned by Sonic hedgehog (Shh), a morphogen that, like L–R patterning, has been argued to require cilia. These observations prompted examination of cilia morphology, which was found to be abnormal in the three gpg mutant lines examined. The results suggest that aberrant cilia function is a potential underlying cause of the gasping phenotype, and several human syndromes with gasping-like features. Although the screen's intent—to identify causes of CHD—has yet to be met, the unexpected outcomes are equally as important, and arguably more intriguing.

Intelligent Screening (Automated image-based phenotypic analysis in zebrafish embryos by Andreas Vogt, Andrzej Cholewinski, Xiaoqiang Shen, Scott G. Nelson, John S. Lazo, Michael Tsang, and Neil A. Hukriede, Dev Dyn238:656–663) Anyone who has screened large numbers of embryos for quantifiable phenotypes knows the process can be slow, laborious, and not entirely objective. Hukriede's group has remedied these problems by optimizing Cognitive Network Technology (CNT), an artificial-intelligence based image analysis method originally designed for examining satellite images. Tg(fli1:EGFP)y1 zebrafish embryos, which express enhanced green fluorescence protein (EGFP) in developing vasculature, were plated into 96-well plates, and fluorescent images acquired by an automated high-content reader. CNT was taught to pick out intersegmental vessels (ISVs) within the context of whole embryos, and the total area, length, and area relative to embryo size was reported. As proof-of-principle, embryos subjected to the vascular endothelial growth factor (VEGF) receptor antagonist SU4312 and the microtubule perturbing agent 2-methoxy estradiol (2-OMe E2) disrupted ISV development as predicted at previously reported concentrations. In addition, another microtubule perturbing agent, (−)-pironetin, whose affects on vasculature development had not yet been examined, was found to behave similarly to 2-OMe E2. The system also handily analyzed fish in nearly any orientation, and eliminated wells with erroneous loading, toxicity, or embryos oriented so the ISV was not visible. The work proves that CNT is an objective, high throughput screening method that can pick up hard to detect phenotype subtleties. Diligent technicians who painstakingly sorted embryos will now be free to work on other things.