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 23 December 2017 https://www.biorxiv.org/content/early/2017/12/23/218487

Article now published in PLOS Biology at http://dx.doi.org/10.1371/journal.pbio.2005086

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

Posted on: 18 February 2018 , updated on: 20 February 2018

Read preprint (1 votes)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

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

Register here

preLists in the developmental biology category:

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)

 



List by Nándor Lipták

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

Society for Developmental Biology 79th Annual Meeting

Preprints at SDB 2020

 



List by Irepan Salvador-Martinez, Martin Estermann

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EDBC Alicante 2019

Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.

 



List by Sergio Menchero et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve

Pattern formation during development

The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.

 



List by Alexa Sadier

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

 



List by Shikha Nayar

Also in the genetics category:

Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University

This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.

 



List by Nándor Lipták

20th “Genetics Workshops in Hungary”, Szeged (25th, September)

In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf

 



List by Nándor Lipták

2nd Conference of the Visegrád Group Society for Developmental Biology

Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)

 



List by Nándor Lipták

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill
Close