Menu

Close

Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth

Alberto Rosello-Diez, Linda Madisen, Sebastien Bastide, Hongkui Zeng, Alexandra L Joyner

Preprint posted on December 23, 2017 https://www.biorxiv.org/content/early/2017/12/23/218487

Ever wonder how your left and right limbs grow to be the same length and never wildly out of proportion with the rest of your body? A new preprint investigates the mechanisms controlling limb-to-limb and limb-to-body ratios in the mouse.

Selected by Natalie Dye

Background:

What determines organ size remains a fascinating open question in development. Organ growth can be promoted by signals released from the organ itself (intrinsic regulators like morphogens, Hh, Wnt, etc) and often also by signals originating from elsewhere (extrinsic regulators such insulin-like growth factor, IGF). The importance of the interplay between intrinsic and extrinsic inputs into organ growth is perhaps best exemplified by paired organs, such as the limbs. While the left and right limbs grow in distant parts of the animal, their growth is exquisitely matched, even if one side is injured during development. Furthermore, their size must be properly scaled with the body if they are going to be effective at tasks like locomotion.

 

Results from the preprint:

The authors of this preprint develop a genetic technique for inducibly inhibiting proliferation in a fraction of cells of the left limb of a developing mouse – specifically chondrocytes, the cells that make the initial cartilage templates of the bone. They discovered that above a certain threshold for insult, the neighboring (genetically unaffected) chondrocytes proliferate more to compensate for the lower density of cells in left limb. Furthermore, the overall body size (including the right limb) decreases by 10%. Injecting IGF rescues the reduction in body size; but the limbs are still coordinated with each other and now proportionally slightly too small for the body. Thus, upon mosaic unilateral limb insult, a drop in IGF (originating from the placenta) is required to maintain normal body:limb proportions, but something else maintains left/right symmetry.

My two cents:

Both compensatory proliferation, as well as systemic inputs into limb/limb and limb/body coordination have been studied extensively in the Drosophila wing, which is my own system. Thus, I can’t help but make comparisons, and actually there are some really important differences.

Local Compensation

In the wing, compensatory proliferation has been observed when cell death is ectopically activated or there is significant tissue loss from injury. In a mosaic situation more analogous to this study, usually faster growing wing cells actually kill their slower neighbors and take over the tissue (so-called cell competition). Importantly, because the perturbed chondrocytes are not dying, the compensation observed in the limb is not really analogous. In contrast, the data indicate that chondrocytes are somehow sensitive to cell density. How does that work? The authors suggest it’s because the arrested cells are sending out an “alarm” signal that must accumulate to some concentration to be active. But maybe it’s more like quorum sensing, where all cells are secreting a signal whose concentration is then a readout of cell density? Or maybe the “signal” is actually mechanical in nature.

Systemic coordination

This work also highlights the existence of a dynamic inter-organ signaling network underlying not only limb-limb coordination but overall body size control – something that has been a hot area of research in Drosophila but is far less understood in vertebrates. The finding that the growth of a limb – something that could be considered non-essential – influences overall body size in a vertebrate is striking. How the limbs communicate to the placenta to regulate IGF secretion will be a key focus for future work. In addition, we still need to figure out how left and right sides are coordinated! This work rules out the possibility that IGF mediates this symmetry, but what about other signals emanating from the placenta? The authors favor the idea that there is direct signaling between the two sides, but there is not yet data (in any system) for how that may work.

In Drosophila, size matching of the adult organ precursors (the so-called “imaginal” tissues) is thought occur via the brain, rather than via direct communication between imaginal tissues. Injury to these tissues causes the upregulation of a relaxin called Dilp8, which travels to the brain to inhibit steroid hormone production. High levels of steroid are required to end the larval growth phase, but lower levels are required for normal (but not regenerative) imaginal growth. Thus, by inhibiting steroid production, Dilp8 not only gives the injured tissue more time to recover (by extending the larval growth phase), but it also prevents the uninjured paired organs from over-growing during this extended growth phase (by depriving them of a key signal that the injured tissue doesn’t seem to need). No such relaxin was found induced in this analogous scenario in the mouse, however, so left/right coordination remains a mystery.

Wrap up

In sum, this work provides fascinating and important new insight into intrinsic and extrinsic regulation of organ growth in a vertebrate system. The experimental approach developed here will be very useful for future investigations into the molecular mechanisms underlying growth control and can presumably also be extended to other paired organs. I look forward to their future discoveries!

 

References for the Drosophila work I mentioned:

Fogarty CE, Bergmann A. “Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease.” Cell Death Differ. 2017. doi: 10.1038/cdd.2017.47.

Clavería C, Torres M. “Cell Competition: Mechanisms and Physiological Roles.” Annu Rev Cell Dev Biol. 2016. doi: 10.1146/annurev-cellbio-111315-125142

Colombani J, Andersen DS, Léopold P. “Secreted peptide Dilp8 coordinates Drosophila tissue growth with developmental timing. Science. 2012. doi: 10.1126/science.

Garelli A, Gontijo AM, Miguela V, Caparros E, Dominguez M. “Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation.” Science 2012. doi: 10.1126/science.

Vallejo DM, Juarez-Carreño S, Bolivar J, Morante J, Dominguez M. “A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3.” Science 2015. doi: 10.1126/science.aac6767

Jacob S. Jaszczak, Jacob B. Wolpe, Anh Q. Dao, Halme A. “Nitric Oxide Synthase Regulates Growth Coordination During Drosophila melanogaster Imaginal Disc Regeneration”. Genetics. 2015. doi:  10.1534/genetics.115.178053

 

preLighter Anna Kicheva has also highlighted this preprint – check out her highlight here.

 

Tags: compensatory proliferation, developing limb, growth control, mouse, organ size, symmetric growth

Read preprint (1 votes)




  • Have your say

    Your email address will not be published. Required fields are marked *

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    A novel mechanism of gland formation in zebrafish involving transdifferentiation of renal epithelial cells and live cell extrusion

    Richard W Naylor, Alan J Davidson



    Selected by Giuliana Clemente

    1

    An intrinsic cell cycle timer terminates limb bud outgrowth

    Joseph Pickering, Kavitha Chinnaiya, Constance A Rich, et al.



    Selected by Ashrifia Adomako-Ankomah

    1

    Fbxw7 is a critical regulator of Schwann cell myelinating potential

    Breanne L Harty, Fernanda Coelho, Sarah D Ackerman, et al.



    Selected by Yen-Chung Chen

    Kinetic sculpting of the seven stripes of the Drosophila even-skipped gene

    Augusto Berrocal, Nicholas C Lammers, Hernan G Garcia, et al.



    Selected by Erik Clark

    TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila.

    Byoungchun Lee, Elizabeth C Barretto, Savraj S Grewal



    Selected by Sarah Bowling

    The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization

    Sarah Herberg, Krista R Gert, Alexander Schleiffer, et al.



    Selected by James Gagnon

    Functional testing of a human PBX3 variant in zebrafish reveals a potential modifier role in congenital heart defects

    Gist H. Farr III, Kimia Imani, Darren Pouv, et al.



    Selected by Hannah Brunsdon

    Mitotic chromosome alignment is required for proper nuclear envelope reassembly

    Cindy L Fonseca, Heidi LH Malaby, Leslie A Sepaniac, et al.



    Selected by Maiko Kitaoka

    Timed collinear activation of Hox genes during gastrulation controls the avian forelimb position

    Chloe Moreau, Paolo Caldarelli, Didier Rocancourt, et al.



    Selected by Wouter Masselink

    WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids

    Anna Yoney, Fred Etoc, Albert Ruzo, et al.



    Selected by Sundar Naganathan

    Human macrophages survive and adopt activated genotypes in living zebrafish

    Colin D. Paul, Alexus Devine, Kevin Bishop, et al.



    Selected by Giuliana Clemente

    1

    Altering the temporal regulation of one transcription factor drives sensory trade-offs

    Ariane Ramaekers, Simon Weinberger, Annelies Claeys, et al.



    Selected by Mariana R.P. Alves

    Presence of midline cilia supersedes the expression of Lefty1 in forming the midline barrier during the establishment of left-right asymmetry

    Natalia A Shylo, Dylan A Ramrattan, Scott D Weatherbee



    Selected by Hannah Brunsdon

    Genetic compensation is triggered by mutant mRNA degradation

    Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, et al.



    Selected by Andreas van Impel

    1

    Cellular Crowding Influences Extrusion and Proliferation to Facilitate Epithelial Tissue Repair

    Jovany Jeomar Franco, Youmna Maryline Atieh, Chase Dallas Bryan, et al.



    Selected by Helen Weavers

    Photoperiod sensing of the circadian clock is controlled by ELF3 and GI

    Usman Anwer, Amanda Davis, Seth Jon Davis, et al.



    Selected by Annika Weimer

    Also in the genetics category:

    Super-Mendelian inheritance mediated by CRISPR/Cas9 in the female mouse germline

    Hannah A. Grunwald, Valentino M. Gantz, Gunnar Poplawski, et al.



    Selected by Rebekah Tillotson

    The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization

    Sarah Herberg, Krista R Gert, Alexander Schleiffer, et al.



    Selected by James Gagnon

    Functional testing of a human PBX3 variant in zebrafish reveals a potential modifier role in congenital heart defects

    Gist H. Farr III, Kimia Imani, Darren Pouv, et al.



    Selected by Hannah Brunsdon

    A robust method for transfection in choanoflagellates illuminates their cell biology and the ancestry of animal septins

    David Booth, Heather Middleton, Nicole King



    Selected by Maya Emmons-Bell

    SWI/SNF remains localized to chromatin in the presence of SCHLAP1

    Jesse R Raab, Keriayn N Smith, Camarie C Spear, et al.



    Selected by Carmen Adriaens

    1

    Genetic compensation is triggered by mutant mRNA degradation

    Mohamed El-Brolosy, Andrea Rossi, Zacharias Kontarakis, et al.



    Selected by Andreas van Impel

    1

    Cellular Crowding Influences Extrusion and Proliferation to Facilitate Epithelial Tissue Repair

    Jovany Jeomar Franco, Youmna Maryline Atieh, Chase Dallas Bryan, et al.



    Selected by Helen Weavers

    Limb- and tendon-specific Adamtsl2 deletion identifies a soft tissue mechanism modulating bone length

    Dirk Hubmacher, Stetson Thacker, Sheila M Adams, et al.



    Selected by Alberto Rosello-Diez

    Cancer modeling by Transgene Electroporation in Adult Zebrafish (TEAZ)

    Scott J Callahan, Stephanie Tepan, Yan M Zhang, et al.



    Selected by Hannah Brunsdon

    1

    PDX Finder: A Portal for Patient-Derived tumor Xenograft Model Discovery

    Nathalie Conte, Jeremy Mason, Csaba Halmagyi, et al.



    Selected by Carmen Adriaens

    Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin

    Jacob Daane, Jennifer Lanni, Ina Rothenberg, et al.



    Selected by Alberto Rosello-Diez

    1

    Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of cell division, differentiation, and loss

    Judy Martin, Erin Nicole Sanders, Paola Moreno-Roman, et al.



    Selected by Natalie Dye

    F-actin patches nucleated on chromosomes coordinate capture by microtubules in oocyte meiosis

    Mariia Burdyniuk, Andrea Callegari, Masashi Mori, et al.



    Selected by Binyam Mogessie

    Comprehensive characterization of transcript diversity at the human NODAL locus

    Scott D Findlay, Lynne-Marie Postovit



    Selected by Christian Ramos

    Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth

    Alberto Rosello-Diez, Linda Madisen, Sebastien Bastide, et al.



    Selected by Natalie Dye

    Precise temporal regulation of alternative splicing during neural development

    Sebastien M Weyn-Vanhentenryck, Huijuan Feng, Dmytro Ustianenko, et al.



    Selected by James Gagnon
    Close

    We want to make our website, and the services we provide, useful and reliable. This sometimes involves placing small amounts of information called cookies on the device you used to access the internet. If you continue to use this website we will assume you are happy to accept our cookies.

    Accept