The first Development issue of the year is now complete! Here are the highlights:
Micro-lenses focus on cataract development
Cataracts have many potential risk factors but the molecular mechanisms underlying their development are unclear. Aggregates of lens epithelial cells (LECs) derived from human pluripotent stem cells (hPSCs) are a potentially powerful in vitro tool to tackle this problem, but existing protocols have a number of shortcomings, including the aggregates’ inability to focus light. Michael O’Connor and colleagues describe an efficient system for the derivation of LECs from hPSCs, and the subsequent creation of light-focusing ‘micro-lenses’ (dev155838). The cell surface marker ROR1 allows for sorting and purification of LECs, which are then cultured as spherical aggregates. Over the course of around three weeks, the aggregates develop the ability to focus light, associated with the expression of crystalline genes and anatomical maturation to mimic lens morphology in vivo. The micro-lenses promise to be clinically relevant, as shown by an analysis of Vx-770, an emerging cystic fibrosis drug that has an as-yet-unclear association with cataract formation. The authors find that culturing with high concentrations of Vx-770 reduces the light-focusing ability of micro-lenses. hPSC-derived micro-lenses therefore provide a powerful in vitro model for research into lens disorders, their risk factors and their molecular underpinnings.
Plant miRNAs: the root of interspecies variation
Plant roots have evolved a variety of anatomical patterns. For example, it is known that the number of root cortical layers varies amongst plant species. But what are the genetic mechanisms that underlie such morphological differences? Raffaele Dello Ioio and colleagues investigate this by analysing root development in Arabidopsis thaliana and Cardamine hirsuta, a genetically tractable close relative of Arabidopsis (dev153858). They first show that, unlike Arabidopsis (which has a single cortical layer), Cardamine has two cortical layers that arise during embryogenesis from a tissue with mixed cortical/endodermal (CEM) identity. They further reveal that Arabidopsis mutants in which the miRNA biogenesis machinery is perturbed also exhibit an additional cortical layer, likely owing to ectopic expression of the HD-ZIPIII transcription factor PHABULOSA (PHB), which is known to be regulated by the microRNA miR165/6. Following this, the authors show that HD-ZIPIII factors are required in the Cardamine CEM tissue for double cortex formation and that the activity domain of miR165/6 differs between the two species; the absence of miR165/6 in Cardamine CEM tissue allows a broader expression domain of PHB, resulting in the development of an extra cortical layer. Together, these findings highlight that variations in miRNA distribution can lead to differences in plant morphology.
All agog for zebrafish Nanog
The Nanog transcription factor is a core regulator of pluripotency in early mammalian embryos, but its role in other vertebrates – which may offer more tractable models for how it works in embryogenesis – has remained unclear. In zebrafish, Nanog morphants fail to complete gastrulation. While a requirement in extra-embryonic tissue development was suggested to underlie this effect, an additional role in zygotic genome activation in the embryo proper has also been proposed. Now, in this issue, two groups report the generation of zebrafish nanog mutants using TALENs, and describe their effects on embryonic and extra-embryonic tissues during development.
James Gagnon, Kamal Obbad and Alexander Schier show that maternal-zygotic (MZ) nanog mutants arrest at gastrulation, phenocopying the morphants, and that Nanog’s function is provided maternally (dev147793). MZnanog mutants fail to normally form the yolk syncytial layer (YSL), an extra-embryonic tissue that attaches the embryo to the yolk, and fail to express key YSL genes while also showing reduced expression of a subset of early zygotic genes within the embryo. Supporting the argument of a predominantly extra-embryonic functional requirement, wild-type blastoderms fail to undergo epiboly when transplanted onto MZnanog mutant yolk cells, while mutant blastoderms transplanted to wild-type yolk cells undergo epiboly. Finally, MZnanog mutant cells proliferate and differentiate into derivatives of all germ layers when transplanted into wild-type hosts, and are detectable in the adult using CRISPR lineage tracing.
Daria Onichtchouk and colleagues show that MZnanog mutants are arrested in gastrulation movements, and exhibit an increase in cell death (dev155366). Gastrulation arrest in the mutants is accompanied by a failure to properly organise the microtubule and actin cytoskeletons in the yolk. In the absence of Nanog, maternal RNAs fail to degrade; this failure can be rescued by mir-430. The authors show that injection of mxtx2 or miR-430 mRNA into the 1-cell stage embryo can rescue the failure of epiboly, but not cell survival, in the MZnanog mutants. While MZnanog mutant cells can differentiate when transplanted into the wild-type embryos, viability is substantially reduced compared with co-injected wild-type cells, suggesting an autonomous role for Nanog in embryonic cell survival.
Taken together, these papers extend our understanding of Nanog’s relative roles in embryonic and extra-embryonic tissues in the fish, and provide a platform for further comparison with other vertebrate models.
And one last thing
In his Editorial, Olivier Pourquié takes stock of his nine years as Editor in Chief of Development, highlighting the key changes that have been implemented by the journal during this period and reflecting on how the field has changed over this time. Olivier also discusses what’s in store for the journal this year, before he steps down as Editor in Chief in September.
An interview with Cliff Tabin
Cliff Tabin is George Jacob and Jacqueline Hazel Leder Professor and Chairman of the Department of Genetics at Harvard Medical School. His lab aims to understand the genetic control of morphogenesis during embryonic development and its change over evolutionary time. We met Cliff at the Pan-American Society for Evolutionary Developmental Biology’s second biennial meeting, held in August 2017, and heard about how he got into development, how a long-standing interest in the limb has been complemented by ventures into new models, and why he thinks we are in a golden age for evo-devo. Read the Spotlight article here.
Towards stem cell based therapies for Parkinson’s disease
Treating neurodegenerative diseases with cell transplantation has been within reach since the first pioneering clinical trials in which dopamine neuron progenitors from the fetal brain were transplanted to individuals with Parkinson’s disease. However, the use of fetal tissue is problematic in terms of low availability and high variability, and it is also associated with ethical concerns that vary between countries. For decades, the field has therefore investigated new scalable source of therapeutic cells from stem cells or via reprogramming. Here, Malin Parmar, discusses how it is now possible to generate authentic midbrain dopaminergic neurons from pluripotent stem cells and how clinical trials using such cells are rapidly approaching.
Mechanisms of erythrocyte development and regeneration: implications for regenerative medicine and beyond
Hemoglobin-expressing erythrocytes (red blood cells) act as fundamental metabolic regulators by providing oxygen to cells and tissues throughout the body. Whereas the vital requirement for oxygen to support metabolically active cells and tissues is well established, almost nothing is known regarding how erythrocyte development and function impact regeneration. Furthermore, many questions remain unanswered relating to how insults to hematopoietic stem/progenitor cells and erythrocytes can trigger a massive regenerative process termed ‘stress erythropoiesis’ to produce billions of erythrocytes. In their Review, Emery Bresnick and colleagues discuss the cellular and molecular mechanisms governing erythrocyte development and regeneration, and highlight the potential links between these events and other regenerative processes.
mTOR signaling in stem and progenitor cells
The mammalian target of rapamycin (mTOR) senses nutrients and growth factors to coordinate cell growth, metabolism and autophagy. Extensive research has mapped the signaling pathways regulated by mTOR that are involved in human diseases, such as cancer, and in diabetes and ageing. Recently, however, new studies have demonstrated important roles for mTOR in promoting the differentiation of adult stem cells, driving the growth and proliferation of stem and progenitor cells, and dictating the differentiation program of multipotent stem cell populations. In their Review, Jenna Jewell and co-workers review these advances, providing an overview of mTOR signaling and its role in murine and human stem and progenitor cells.