Developmental biology

  • Letter |

    Transcriptional enhancers are segments of regulatory DNA located some distance from the coding region of a gene, and several of them may sometimes serve apparently redundant functions. These authors demonstrate in Drosophila that such 'redundant' enhancers, by contributing higher overall levels of transcription, ensure robustness of phenotypes against both genetic and environmental perturbations, for example mutations in other genes or temperature changes that would otherwise lead to aberrant development.

    • Nicolás Frankel
    • , Gregory K. Davis
    •  & David L. Stern
  • Letter |

    The protein ephrin-B2 is known to be upregulated during angiogenesis — the growth of new blood vessels — but its precise function has been unclear. Here it is shown that signalling through ephrin-B2 controls vessel sprouting. Mechanistically, ephrin-B2 seems to function in part by regulating the internalization of vascular endothelial growth factor receptors (VEGFRs). The results indicate that blocking ephrin-B2 signalling might be an alternative to blocking VEGFR function to disrupt angiogenesis in tumours.

    • Yingdi Wang
    • , Masanori Nakayama
    •  & Ralf H. Adams
  • Letter |

    The protein ephrin-B2 is known to be upregulated during angiogenesis — the growth of new blood vessels — but its precise function has been unclear. Here it is shown that signalling through ephrin-B2 controls vessel sprouting. Mechanistically, ephrin-B2 seems to function in part by regulating the internalization of vascular endothelial growth factor receptors (VEGFRs). The results indicate that blocking ephrin-B2 signalling might be an alternative to blocking VEGFR function to disrupt angiogenesis in tumours.

    • Suphansa Sawamiphak
    • , Sascha Seidel
    •  & Amparo Acker-Palmer
  • Article |

    MicroRNAs, which regulate gene expression, are transcribed as longer sequences that are processed to produce the mature form. Two nuclease enzymes, Drosha and Dicer, are known to act sequentially to trim the microRNA to size. Here, however, a subset of microRNAs that includes miR-451, important for erythropoiesis, is found to be processed independently of Dicer. Rather, the Argonaute protein — part of the complex that aligns microRNA and messenger RNA — carries out the secondary cleavage.

    • Sihem Cheloufi
    • , Camila O. Dos Santos
    •  & Gregory J. Hannon
  • Letter |

    Notch and Delta are transmembrane proteins that allow neighbouring cells to communicate during development. Here, quantitative time-lapse microscopy has been used to show that the response of Notch to Delta on a neighbouring cell is graded, whereas its response to Delta on the same cell is sharp and occurs at a fixed threshold. A mathematical model explores how this new design principle enhances the sharpness of developmental boundaries set by classical lateral inhibition.

    • David Sprinzak
    • , Amit Lakhanpal
    •  & Michael B. Elowitz
  • Article |

    Induced pluripotent stem cells (iPSCs) are generated by the enforced expression of particular transcription factors in somatic cells. The extent to which such cells are equivalent to embryonic stem (ES) cells is an open question. Here, genetically identical mouse ES cells and iPSCs have been compared; the overall expression patterns of messenger RNAs and microRNAs are the same, with the exception of a few transcripts encoded within an imprinted gene cluster on chromosome 12qF1.

    • Matthias Stadtfeld
    • , Effie Apostolou
    •  & Konrad Hochedlinger
  • Letter |

    Before mating, a yeast cell must detect a partner cell that is close enough and expresses sufficiently large amounts of a sex pheromone. The mating decision is an all-or-none, switch-like response to pheromone concentration. It is now shown that this decision involves the competition of one kinase and one phosphatase enzyme for multiple phosphorylation sites on a 'scaffold' protein. The results should prompt a re-evaluation of the role of related signalling molecules that have been implicated in cancer.

    • Mohan K. Malleshaiah
    • , Vahid Shahrezaei
    •  & Stephen W. Michnick
  • Letter |

    Primary cilia are tiny hair-like structures expressed on the surface of eukaryotic cells. They participate in a range of processes, such as sensing the extracellular environment and regulating signalling pathways during development. Here, a functional genomic screen is presented that used RNA interference to identify human genes involved in controlling ciliogenesis. Several positive and negative ciliogenesis modulators with broad-ranging functions were found.

    • Joon Kim
    • , Ji Eun Lee
    •  & Joseph G. Gleeson
  • Letter |

    Complex heritable traits — such as human height and many human diseases — are caused by multiple genetic loci, each with small effects. It is hard to identify such loci, however, because of a lack of statistical power. Now, a method has been developed to overcome this problem. The method has been applied to chemical resistance traits and mitochondrial function in yeast, and has identified loci for each of these phenotypes.

    • Ian M. Ehrenreich
    • , Noorossadat Torabi
    •  & Leonid Kruglyak
  • Letter |

    The ovarian hormones oestrogen and progesterone increase breast cancer risk but the cellular mechanisms are unclear. Here it is shown that the size of the mammary stem cell pool in mice is regulated by steroid hormone signalling, although these cells lack the receptors for oestrogen and progesterone. The augmented pool could lead to clonal expansion of a mutated cell, possibly accounting for the increased incidence of breast cancer associated with pregnancy.

    • Marie-Liesse Asselin-Labat
    • , François Vaillant
    •  & Jane E. Visvader
  • Article |

    Here, the generation and evolution of the complex spotted wing pattern of Drosophila guttifera are investigated. The findings show that wing spots are induced by the Wingless morphogen, and that the elaborate spot pattern evolved from simpler schemes by co-option of Wingless expression at new sites. This type of process is likely to occur in other animals, too.

    • Thomas Werner
    • , Shigeyuki Koshikawa
    •  & Sean B. Carroll
  • Article |

    In the pancreas, insulin-producing β-cells are long-lived and generally replicate seldom. They can do so, however, after increased metabolic demand or after injury. Here, a new transgenic model is developed in which β-cells are nearly completely ablated in mice. If given insulin, these mice survive, and grow new β-cells. Lineage-tracing shows that these new β-cells come from α-cells, revealing a previously disregarded degree of pancreatic cell plasticity.

    • Fabrizio Thorel
    • , Virginie Népote
    •  & Pedro L. Herrera
  • Letter |

    Study of two specimens of the feathered dinosaur Similicaudipteryx shows that the morphology of dinosaur feathers changed dramatically as the animals matured. Moreover, the morphology of feathers in dinosaurs was much more varied than one would expect from looking at feathers in modern birds.

    • Xing Xu
    • , Xiaoting Zheng
    •  & Hailu You
  • Letter |

    Although several synaptic adhesion proteins have been identified as genetic risk factors in schizophrenia, it is unclear as to what role they play in disease progression. Here, it is shown that two such proteins — neuregulin 1 and its receptor ErbB4 — function to regulate the connectivity of specific cortical circuits. The study not only implicates these proteins in the wiring of inhibitory synapses, about which little is known, but also provides a new perspective on their involvement in schizophrenia.

    • Pietro Fazzari
    • , Ana V. Paternain
    •  & Beatriz Rico
  • Letter |

    Self-fertilisation (selfing) in plants is prevented mainly by the self-incompatibility recognition system, which consists of male and female specificity genes and modifier genes. Selfing does occur in Arabidopsis plants, but it is not known how it arose. Here it is reported that selfing in Arabidopsis results from a geographically widespread, 213-base-pair inversion within the male specificity gene. When this inversion is returned to its original orientation, selfing is prevented once more.

    • Takashi Tsuchimatsu
    • , Keita Suwabe
    •  & Kentaro K. Shimizu
  • Article |

    Prevailing models propose that coronary arteries in the developing heart are formed from progenitor cells originating in the proepicardium. It is found here, however, that these arteries arise from angiogenic sprouts of the major vein that returns circulating blood to the embryonic heart. Thus some differentiated venous cells retain developmental plasticity and respond to local signals to convert to coronary arteries, capillaries and veins.

    • Kristy Red-Horse
    • , Hiroo Ueno
    •  & Mark A. Krasnow
  • Letter |

    Zebrafish are able to replace lost heart muscle efficiently, and are used as a model to understand why natural heart regeneration — after a heart attack, for instance — is blocked in mammals. Here, and in an accompanying paper, genetic fate-mapping approaches reveal which cell population contributes prominently to cardiac muscle regeneration after an injury approximating myocardial infarction. The results show that cardiac muscle regenerates through activation and expansion of existing cardiomyocytes, without involving a stem-cell population.

    • Chris Jopling
    • , Eduard Sleep
    •  & Juan Carlos Izpisúa Belmonte
  • Letter |

    Zebrafish are able to replace lost heart muscle efficiently, and are used as a model to understand why natural heart regeneration — after a heart attack, for instance — is blocked in mammals. Here, and in an accompanying paper, genetic fate-mapping approaches reveal which cell population contributes prominently to cardiac muscle regeneration after an injury approximating myocardial infarction. The results show that cardiac muscle regenerates through activation and expansion of existing cardiomyocytes, without involving a stem-cell population.

    • Kazu Kikuchi
    • , Jennifer E. Holdway
    •  & Kenneth D. Poss
  • Article |

    In the mammalian brain, the subventricular zone (SVZ) produces neural progenitor cells that migrate into the cortex to populate the upper layers. In humans this region is massively expanded, producing an outer SVZ (OSVZ). Here, live-cell imaging of developing human tissue was used to show that the OSVZ has similar characteristics to the SVZ, with progenitor cells proliferating in a way that depends on the Notch protein. The findings have implications for our understanding of how the complex human brain evolved.

    • David V. Hansen
    • , Jan H. Lui
    •  & Arnold R. Kriegstein
  • Letter |

    To study the changes in chromatin structure that accompany zygotic genome activation and pluripotency during the maternal–zygotic transition (MZT), the genomic locations of histone H3 modifications and RNA polymerase II have been mapped during this transition in zebrafish embryos. H3 lysine 27 trimethylation and H3 lysine 4 trimethylation are only detected after MZT; evidence is provided that the bivalent chromatin domains found in cultured embryonic stem cells also exist in embryos.

    • Nadine L. Vastenhouw
    • , Yong Zhang
    •  & Alexander F. Schier
  • Letter |

    A genome-wide RNA interference screen to systematically test the genetic basis for formation and function of the Drosophila muscle is described. A role in muscle for 2,785 genes is identified; many of these genes are phylogenetically conserved.

    • Frank Schnorrer
    • , Cornelia Schönbauer
    •  & Barry J. Dickson
  • Letter |

    Genotype and phenotype cannot be connected simply by one-to-one mapping; instead they are linked by the nonlinear process of development. Here, a computational model is described — based on real data about the development of seal teeth — that attempts to combine the three. The results show that a few genetic parameters regulating signalling during cusp development may explain variation among individuals. But a cellular parameter regulating epithelial growth may explain tooth-to-tooth variation along the jaw.

    • Isaac Salazar-Ciudad
    •  & Jukka Jernvall
  • Letter |

    The organization of Hox clusters in several different reptiles is investigated, showing that the Hox clusters in squamates — lizards and snakes — have unexpectedly accumulated transposable elements, reflecting extensive genomic rearrangements of coding and non coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions.

    • Nicolas Di-Poï
    • , Juan I. Montoya-Burgos
    •  & Denis Duboule
  • Letter |

    An understanding of how fat cells (adipocytes) develop will contribute to our understanding of obesity. The differentiation of committed preadipocytes into adipocytes is known to be controlled by PPARγ and several other transcription factors. But what turns a cell into a preadipocyte? Here, the zinc-finger protein Zfp423 is identified as a transcriptional regulator of preadipocyte determination.

    • Rana K. Gupta
    • , Zoltan Arany
    •  & Bruce M. Spiegelman
  • Letter |

    During development in Arabidopsis plants, populations of shoot stem cells and root stem cells are established at the embryo's apical and basal poles, respectively. PLETHORA genes are master regulators of root fate, but the regulators of shoot fate were unknown. Here, CLASS III HOMEODOMAIN-LEUCINE ZIPPER genes are identified as master regulators of apical/shoot fate, and are shown to be sufficient to convert the embryonic root pole into a second shoot pole.

    • Zachery R. Smith
    •  & Jeff A. Long
  • Letter |

    The unfolded protein response, known to contribute to the defence against infectious agents and toxins, is shown here to protect Caenorhabditis elegans larvae against detrimental effects of the innate immune response to infection with Pseudomonas aeruginosa. The findings establish innate immunity as a physiologically relevant inducer of ER stress during C. elegans development.

    • Claire E. Richardson
    • , Tristan Kooistra
    •  & Dennis H. Kim
  • Letter |

    Sequence variations in a 58-kilobase interval on human chromosome 9p21 have been associated with an increased risk of coronary artery disease. However, this interval contains no protein-coding genes and the mechanism underlying the increased risk has been unclear. Here, the corresponding interval has been deleted from mouse chromosome 4, revealing that this part of the chromosome regulates the cardiac expression of two nearby genes, Cdkn2a and Cdkn2b, and the proliferation dynamics of vascular cells.

    • Axel Visel
    • , Yiwen Zhu
    •  & Len A. Pennacchio
  • Letter |

    The vertebrate body plan shows marked bilateral symmetry, although this can be disrupted in conditions such as scoliosis. Here, a mutation in Rere is found that leads to the formation of asymmetrical somites in mouse embryos; furthermore, Rere is shown to control retinoic acid signalling, which is required to maintain somite symmetry by interacting with Fgf8. The results provide insight into how bilateral symmetry is maintained.

    • Gonçalo C. Vilhais-Neto
    • , Mitsuji Maruhashi
    •  & Olivier Pourquié
  • Letter |

    Here, iPS cell technology is used to study the mechanisms underlying dyskeratosis congenita in humans. Reprogramming restores telomere elongation in dyskeratosis congenita cells despite genetic lesions affecting telomerase. The reprogrammed cells were able to overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal, and multiple telomerase components are targeted by pluripotency-associated transcription factors.

    • Suneet Agarwal
    • , Yuin-Han Loh
    •  & George Q. Daley
  • Letter |

    Endogenous retroviruses (ERVs) are widely dispersed in mammalian genomes, and are silenced in somatic cells by DNA methylation. Here, an ERV silencing pathway independent of DNA methylation is shown to operate in embryonic stem cells. The pathway involves the histone H3K9 methyltransferase ESET and might be important for ERV silencing during the stages in embryogenesis when DNA methylation is reprogrammed.

    • Toshiyuki Matsui
    • , Danny Leung
    •  & Yoichi Shinkai
  • Letter |

    One of two papers showing the generation of haematopoietic stem cells (HSCs) from the ventral wall of the dorsal aorta in live zebrafish embryos. Here, using imaging of live zebrafish, HSCs are shown to emerge directly from the aorta floor. This process does not involve cell division but movement of single endothelial cells out of the aorta ventral wall into the sub aortic space, where they transform into haematopoietic cells.

    • Karima Kissa
    •  & Philippe Herbomel
  • Letter |

    De novo emergence of phenotypically defined haematopoietic stem cells (Sca1+, c kit+, CD41+) directly from ventral aortic haemogenic endothelial cells is shown in mice. Although the study did not visualize live embryos, it instead developed a dissection procedure to visualize the deeply located aorta.

    • Jean-Charles Boisset
    • , Wiggert van Cappellen
    •  & Catherine Robin
  • Letter |

    One of two papers showing the generation of haematopoietic stem cells (HSCs) from the ventral wall of the dorsal aorta in live zebrafish embryos. Here, combined fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry identify and isolate the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. HSCs generated from this haemogenic endothelium are the lineal founders of virtually all of the adult haematopoietic system.

    • Julien Y. Bertrand
    • , Neil C. Chi
    •  & David Traver
  • Article |

    Pancreatic β-cells release insulin, which controls energy homeostasis in vertebrates, and its lack causes diabetes mellitus. The transcription factor neurogenin 3 (Neurog3) initiates differentiation of β-cells and other islet cell types from pancreatic endoderm; here, the transcription factor Rfx6 is shown to direct islet cell differentiation downstream of Neurog3 in mice and humans. This may be useful in efforts to generate β-cells for patients with diabetes.

    • Stuart B. Smith
    • , Hui-Qi Qu
    •  & Michael S. German
  • Letter |

    The transcription factor Tbx3 is shown to significantly improve the quality of induced pluripotent stem (iPS) cells. Tbx3 binding sites in embryonic stem cells are present in genes involved in pluripotency and reprogramming factors. Furthermore, there are intrinsic qualitative differences in iPS cells generated by different methods in terms of their pluripotency, thus highlighting the need to rigorously characterize iPS cells beyond in vitro studies.

    • Jianyong Han
    • , Ping Yuan
    •  & Bing Lim
  • Letter |

    Heterozygous mutations in the gene encoding CHD7, an ATP-dependent chromatin-remodelling protein, result in CHARGE syndrome — a disorder characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. In humans and Xenopus, CHD7 is now shown to be essential for the formation of multipotent migratory neural crest and for activating the transcriptional circuitry of the neural crest; shedding light on the pathoembryology of CHARGE syndrome.

    • Ruchi Bajpai
    • , Denise A. Chen
    •  & Joanna Wysocka
  • Article |

    Age-associated changes in stem cell supportive niche cells are shown to deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment.

    • Shane R. Mayack
    • , Jennifer L. Shadrach
    •  & Amy J. Wagers
  • Article |

    Mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. Here, mature differentiated cells are directed, via a combination of a few transcription factors (distinct from those described for generating iPS cells), to form functional neurons in vitro, without having to revert the fibroblasts to an embryonic state.

    • Thomas Vierbuchen
    • , Austin Ostermeier
    •  & Marius Wernig
  • Letter |

    The extent of epigenetic reprogramming in mammalian primordial germ cells (PGCs) and in early embryos, and its molecular mechanisms, are poorly understood. DNA methylation profiling in PGCs now reveals a genome–wide erasure of methylation, with female PGCs being less methylated than male ones. A deficiency of the cytidine deaminase AID interferes with the genome–wide erasure of DNA methylation, indicating that AID has a critical function in epigenetic reprogramming.

    • Christian Popp
    • , Wendy Dean
    •  & Wolf Reik
  • Letter |

    Progenitor cells sustain the capacity of self-renewing tissues for proliferation while suppressing cell cycle exit and terminal differentiation. DNA methylation is one potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through cell divisions. The DNA methyltransferase 1 and other regulators of DNA methylation are now shown to be essential for epidermal progenitor cell function.

    • George L. Sen
    • , Jason A. Reuter
    •  & Paul A. Khavari
  • Letter |

    Immune homeostasis relies on tight control over the size of a population of regulatory T cells (Treg) that can suppress over-exuberant immune responses. Cells commit to the Treg lineage by upregulating the transcription factor Foxp3. Conserved non-coding DNA sequence elements at the Foxp3 locus are now shown to control the composition, size and maintenance of the Treg cell population.

    • Ye Zheng
    • , Steven Josefowicz
    •  & Alexander Y. Rudensky
  • Article |

    The differentiation of an embryonic stem cell (ESC) requires both suppression of the self-renewal process and activation of the specific differentiation pathway. The let-7 family of microRNAs (miRNAs) are now shown to suppress the self-renewal program in cells that are normally unable to silence this program, whereas introduction of ESC cell cycle regulating miRNAs blocks the action of let-7. Thus, the interplay between these two groups of miRNAs dictates cell fate.

    • Collin Melton
    • , Robert L. Judson
    •  & Robert Blelloch