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Developmental biology - Cell Metabolism|
Placenta equalizes growth rate in embryo
To explore if vertebrates, like ourselves, can coordinate balanced limb growth as insects do, researchers created a bone injury on one hind limb on one side of many baby mice - just before birth. These injuries triggered the inhibition of a gene cell cycle that forms bone cartilage. The result was inhibited bone growth of injured limbs on one side, while normal growth continued on the other. Additionally, on the injured limb, researchers also suppressed gene function to a few of the bone-forming cells, in order to examine the precise response between cartilage and bone cells on the same limb.
Within the injury, researchers observed that those cells not producing cell-cycle suppressor continued to divide above what is normally expected — to compensate for the injured cells. So, overall growth of the affected limb and its side of the body, only mildly slowed down. The signal initiating and driving this hyper-proliferation of cells has not yet been named, but researchers note that once a certain injury threshold was surpassed, the mouse body plan responded proportionately to the number of cells suppressed.
Researchers also found that a reduction in the rate of mouse pup growth correlated to a reduction in insulin-like growth factor signals coming from the placenta. Researchers believe that insulin-like growth factor regulates our overall growth rate and body proportions during embryonic development.
"These results reveal that a response to an insult in development is evolutionarily conserved across species [insects and invertebrates]. This opens new avenues for future research and possible developmental therapies for growth disorders," explains Alberto Roselló-Díez and Alexandra Joyner.
Catch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, injury to individual tissues is followed by local and systemic compensatory mechanisms that allow the damaged tissue to regain normal proportions with other tissues. In vertebrates, local catch-up growth has been described after transient reduction of bone growth, but the underlying cellular responses are controversial. We developed an approach to study catch-up growth in foetal mice in which mosaic expression of the cell cycle suppressor p21 is induced in the cartilage cells (chondrocytes) that drive long-bone elongation. By specifically targeting p21 expression to left hindlimb chondrocytes, the right limb serves as an internal control. Unexpectedly, left–right limb symmetry remained normal, revealing deployment of compensatory mechanisms. Above a certain threshold of insult, an orchestrated response was triggered involving local enhancement of bone growth and systemic growth reduction that ensured that body proportions were maintained. The local response entailed hyperproliferation of spared left limb chondrocytes that was associated with reduced chondrocyte density. The systemic effect involved impaired placental function and IGF signalling, revealing bone–placenta communication. Therefore, vertebrates, like invertebrates, can mount coordinated local and systemic responses to developmental insults that ensure that normal body proportions are maintained.
The coordination of organ growth is necessary to attain correct individual organ sizes and body proportions. While extensive studies in insects have revealed that both intra-organ and inter-organ communication mechanisms are involved in regulating organ growth, vertebrate studies have lagged behind. Here, we developed a new mouse model to examine cellular mechanisms underlying growth regulation after a developmental insult. The cell cycle suppressor p21 was expressed in the cartilage that drives growth of the long bones, targeting the left limb exclusively and leaving the right limb as an internal control. By triggering the insult during the last gestational week, we found that left–right limb symmetry was maintained due to the following 2 compensatory mechanisms: (1) hyperproliferation of the spared cells within the targeted cartilage, which indicates that these cells respond to a signal coming from the arrested cells, and (2) a growth reduction in the rest of the body, an effect that correlates with changes in the levels of placental insulin-like growth factor (IGF) signalling and that can be rescued by boosting placental efficiency. These results reveal that the response to developmental insults is quite evolutionarily conserved across species as well as open new avenues of future research for the development of therapies to treat growth disorders.
Authors: Alberto Roselló-Díez , Linda Madisen, Sébastien Bastide, Hongkui Zeng and Alexandra L. Joyner.
Funding: NIH-NICHD (grant number R21HD083860). Granted to ALJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Human Frontiers Science Program (grant number LT000521/2012-L). Granted to ARD. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Charles Revson Foundation (grant number 15-34). Granted to ARD. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Research targeted gene p21 and reduced its function in cartilage cells of mice left hindlimbs before birth. However, at birth the symmetry between both left and right limbs was normal. This reveals there are mechanisms which adjust cell loss above a certain amount. While cell loss triggered an increase in cell production to the injured bone, simultaneously cell production in the uninjured bone was reduced. This mechanism ensured body proportions remained stable. These results reveal communication exists between bone and placenta. Dox refers to doxycycline which is used to reduce gene expression.
Image credit: Sloan Kettering Institute, New York, New York, USA.