Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains

Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains:
by Samir Merabet, Isma Litim-Mecheri, Daniel Karlsson, Richa Dixit, Mehdi Saadaoui, Bruno Monier, Christine Brun, Stefan Thor, K. Vijayraghavan, Laurent Perrin, Jacques Pradel, Yacine Graba


Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.

A Conserved Developmental Patterning Network Produces Quantitatively Different Output in Multiple Species of Drosophila

A Conserved Developmental Patterning Network Produces Quantitatively Different Output in Multiple Species of Drosophila:
by Charless C. Fowlkes, Kelly B. Eckenrode, Meghan D. Bragdon, Miriah Meyer, Zeba Wunderlich, Lisa Simirenko, Cris L. Luengo Hendriks, Soile V. E. Keränen, Clara Henriquez, David W. Knowles, Mark D. Biggin, Michael B. Eisen, Angela H. DePace


Differences in the level, timing, or location of gene expression can contribute to alternative phenotypes at the molecular and organismal level. Understanding the origins of expression differences is complicated by the fact that organismal morphology and gene regulatory networks could potentially vary even between closely related species. To assess the scope of such changes, we used high-resolution imaging methods to measure mRNA expression in blastoderm embryos of Drosophila yakuba and Drosophila pseudoobscura and assembled these data into cellular resolution atlases, where expression levels for 13 genes in the segmentation network are averaged into species-specific, cellular resolution morphological frameworks. We demonstrate that the blastoderm embryos of these species differ in their morphology in terms of size, shape, and number of nuclei. We present an approach to compare cellular gene expression patterns between species, while accounting for varying embryo morphology, and apply it to our data and an equivalent dataset for Drosophila melanogaster. Our analysis reveals that all individual genes differ quantitatively in their spatio-temporal expression patterns between these species, primarily in terms of their relative position and dynamics. Despite many small quantitative differences, cellular gene expression profiles for the whole set of genes examined are largely similar. This suggests that cell types at this stage of development are conserved, though they can differ in their relative position by up to 3–4 cell widths and in their relative proportion between species by as much as 5-fold. Quantitative differences in the dynamics and relative level of a subset of genes between corresponding cell types may reflect altered regulatory functions between species. Our results emphasize that transcriptional networks can diverge over short evolutionary timescales and that even small changes can lead to distinct output in terms of the placement and number of equivalent cells.

A Protein Complex Network of Drosophila melanogaster

A Protein Complex Network of Drosophila melanogaster: K.G. Guruharsha, Jean-François Rual, Bo Zhai, Julian Mintseris, Pujita Vaidya, Namita Vaidya, Chapman Beekman, Christina Wong, David Y. Rhee, Odise Cenaj, Emily McKillip, Saumini Shah, Mark Stapleton, Kenneth H. Wan, Charles Yu, Bayan Parsa, Joseph W. Carlson, Xiao Chen, Bhaveen Kapadia, K. VijayRaghavan, Steven P. Gygi, Susan E. Celniker, Robert A. Obar, Spyros Artavanis-Tsakonas. Determining the composition of protein complexes is an essential step toward understanding the cell as an integrated system. Using coaffinity purification coupled to mass spectrometry analysis, we....

Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration

Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration: Eirini Trompouki, Teresa V. Bowman, Lee N. Lawton, Zi Peng Fan, Dai-Chen Wu, Anthony DiBiase, Corey S. Martin, Jennifer N. Cech, Anna K. Sessa, Jocelyn L. Leblanc, Pulin Li, Ellen M. Durand, Christian Mosimann, Garrett C. Heffner, George Q. Daley, Robert F. Paulson, Richard A. Young, Leonard I. Zon. BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic linea....

A high-resolution map of human evolutionary constraint using 29 mammals

A high-resolution map of human evolutionary constraint using 29 mammals:

A high-resolution map of human evolutionary constraint using 29 mammals

Nature 478, 7370 (2011). doi:10.1038/nature10530

Authors: Kerstin Lindblad-Toh, Manuel Garber, Or Zuk, Michael F. Lin, Brian J. Parker, Stefan Washietl, Pouya Kheradpour, Jason Ernst, Gregory Jordan, Evan Mauceli, Lucas D. Ward, Craig B. Lowe, Alisha K. Holloway, Michele Clamp, Sante Gnerre, Jessica Alföldi, Kathryn Beal, Jean Chang, Hiram Clawson, James Cuff, Federica Di Palma, Stephen Fitzgerald, Paul Flicek, Mitchell Guttman, Melissa J. Hubisz, David B. Jaffe, Irwin Jungreis, W. James Kent, Dennis Kostka, Marcia Lara, Andre L. Martins, Tim Massingham, Ida Moltke, Brian J. Raney, Matthew D. Rasmussen, Jim Robinson, Alexander Stark, Albert J. Vilella, Jiayu Wen, Xiaohui Xie, Michael C. Zody, Kim C. Worley, Christie L. Kovar, Donna M. Muzny, Richard A. Gibbs, Wesley C. Warren, Elaine R. Mardis, George M. Weinstock, Richard K. Wilson, Ewan Birney, Elliott H. Margulies, Javier Herrero, Eric D. Green, David Haussler, Adam Siepel, Nick Goldman, Katherine S. Pollard, Jakob S. Pedersen, Eric S. Lander & Manolis Kellis

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering

Dpp Signaling Activity Requires Pentagone to Scale with Tissue Size in the Growing Drosophila Wing Imaginal Disc

Dpp Signaling Activity Requires Pentagone to Scale with Tissue Size in the Growing Drosophila Wing Imaginal Disc:

by Fisun Hamaratoglu, Aitana Morton de Lachapelle, George Pyrowolakis, Sven Bergmann, Markus Affolter

The wing of the fruit fly, Drosophila melanogaster, with its simple, two-dimensional structure, is a model organ well suited for a systems biology approach. The wing arises from an epithelial sac referred to as the wing imaginal disc, which undergoes a phase of massive growth and concomitant patterning during larval stages. The Decapentaplegic (Dpp) morphogen plays a central role in wing formation with its ability to co-coordinately regulate patterning and growth. Here, we asked whether the Dpp signaling activity scales, i.e. expands proportionally, with the growing wing imaginal disc. Using new methods for spatial and temporal quantification of Dpp activity and its scaling properties, we found that the Dpp response scales with the size of the growing tissue. Notably, scaling is not perfect at all positions in the field and the scaling of target gene domains is ensured specifically where they define vein positions. We also found that the target gene domains are not defined at constant concentration thresholds of the downstream Dpp activity gradients P-Mad and Brinker. Most interestingly, Pentagone, an important secreted feedback regulator of the pathway, plays a central role in scaling and acts as an expander of the Dpp gradient during disc growth.

Notch/Delta signalling is not required for segment generation in the basally branching insect Gryllus bimaculatus [RESEARCH ARTICLES]

Notch/Delta signalling is not required for segment generation in the basally branching insect Gryllus bimaculatus [RESEARCH ARTICLES]: Franz Kainz, Ben Ewen-Campen, Michael Akam, and Cassandra G. Extavour

Arthropods and vertebrates display a segmental body organisation along all or part of the anterior-posterior axis. Whether this reflects a shared, ancestral developmental genetic mechanism for segmentation is uncertain. In vertebrates, segments are formed sequentially by a segmentation ‘clock’ of oscillating gene expression involving Notch pathway components. Recent studies in spiders and basal insects have suggested that segmentation in these arthropods also involves Notch-based signalling. These observations have been interpreted as evidence for a shared, ancestral gene network for insect, arthropod and bilaterian segmentation. However, because this pathway can play multiple roles in development, elucidating the specific requirements for Notch signalling is important for understanding the ancestry of segmentation. Here we show that Delta, a ligand of the Notch pathway, is not required for segment formation in the cricket Gryllus bimaculatus, which retains ancestral characteristics of arthropod embryogenesis. Segment patterning genes are expressed before Delta in abdominal segments, and Delta expression does not oscillate in the pre-segmental region or in formed segments. Instead, Delta is required for neuroectoderm and mesectoderm formation; embryos missing these tissues are developmentally delayed and show defects in segment morphology but normal segment number. Thus, what initially appear to be ‘segmentation phenotypes’ can in fact be due to developmental delays and cell specification errors. Our data do not support an essential or ancestral role of Notch signalling in segment generation across the arthropods, and show that the pleiotropy of the Notch pathway can confound speculation on possible segmentation mechanisms in the last common bilaterian ancestor.