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Stem cells in the cortex of a mouse embryo (cell nuclei: blue).
© MPI f. Molecular Cell Biology and Genetics/ D. Stenzel.
Our brains pivotal need for iodine & brain stem cells
Max Planck researchers know why iodine deficiency during pregnancy can have disastrous effects.
Without iodine, no thyroid hormones are produced. Thyroid hormones work together with a protein molecule found on brain stem cell surfaces, to enlarge our cerebral cortex.
Humans are higher mammals, and as such, have markedly larger brains than most mammals, except dolphins, some whales, and elephants.
Scientists from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden recently discovered a new mechanism governing brain stem cell proliferation. This mechanism boosts the production of neurons during brain development, causing enlargement of our cerebral cortex – the part of our brain enabling us to speak, think and dream.
The surprising discovery made by the Dresden-based researchers: two components in the stem cell environment – the extracellular matrix and thyroid hormones – work together with an integrin protein molecule found on the stem cell surface. This likely explains why iodine deficiency in pregnant women has disastrous consequences for the unborn child, affecting its brain development adversely – without iodine, no thyroid hormones are produced.
“Our study highlights this relationship [between iodine and thyroid and the extracellular matrix] and provides a potential explanation for the condition neurologists refer to as cretinism [stunted brain development].”
Wieland Huttner, Director, the Max Planck Institute, Dresden.
In the course of evolution, certain mammals, notably humans, have developed larger brains, and therefore more advanced cognitive abilities. Mice, for example, have brains that are around a thousand times smaller than the human one. In this study conducted in cooperation with the Fritz Lipmann Institute in Jena, researchers in Dresden wanted to identify factors that determine brain development, and understand how larger brains have evolved.
A cosy bed for brain stem cells
Brain neurons are generated from stem cells called basal progenitors that proliferate in humans, but not in mice. In humans, basal progenitors are surrounded by a special environment, called the extracellular matrix (ECM), produced by the progenitor basal progenitor stem cells. Like a cosy bed, the ECM accommodates proliferating cells. Mice lack an ECM, which means that they generate fewer neurons and have a smaller brain.
The scientists therefore conducted tests to see whether in mice, basal progenitors start to proliferate if a comparable cell environment is simulated. The result: “We simulated an extracellular matrix for the brain stem cells using a stimulating antibody. This antibody activates an integrin on the cell surface of basal progenitors and thus stimulates their proliferation”, explains Denise Stenzel, who headed the experiments.
Because a requirement of thyroid hormones for proper brain development was previously known, researchers blocked the production of throid hormones in pregnant rats to see the outcome.
Indeed, fewer progenitor stem cells and, consequently, neurons were produced, likely explaining their abnormal brain development in the absence of thyroid hormones.
When the action of these hormones on the integrin was blocked, the ECM-simulating antibody alone was no longer able to induce basal progenitor proliferation.
A combination of ECM and thyroid hormones appears necessary for basal progenitors to proliferate and produce enough neurons for brain development. Human brain stem cells produce the suitable environment.
“That is probably how, in the course of evolution, we humans developed larger brains”, says Wieland Huttner, summing up the study. The research produced another important finding: “We were able to explain the role of iodine in embryonic brain development at the cellular level”, says Denise Stenzel.
Iodine is essential for the production of thyroid hormones, and an iodine deficiency in pregnant women is known to have adverse effects on the brain development of her unborn child.
This work is published in the journal Development.
Neocortex expansion during evolution is associated with the enlargement of the embryonic subventricular zone, which reflects an increased self-renewal and proliferation of basal progenitors. In contrast to human, the vast majority of mouse basal progenitors lack self-renewal capacity, possibly due to lack of a basal process contacting the basal lamina and downregulation of cell-autonomous production of extracellular matrix (ECM) constituents. Here we show that targeted activation of the ECM receptor integrin αvβ3 on basal progenitors in embryonic mouse neocortex promotes their expansion. Specifically, integrin αvβ3 activation causes an increased cell cycle re-entry of Pax6-negative, Tbr2-positive intermediate progenitors, rather than basal radial glia, and a decrease in the proportion of intermediate progenitors committed to neurogenic division. Interestingly, integrin αvβ3 is the only known cell surface receptor for thyroid hormones. Remarkably, tetrac, a thyroid hormone analog that inhibits the binding of thyroid hormones to integrin αvβ3, completely abolishes the intermediate progenitor expansion observed upon targeted integrin αvβ3 activation, indicating that this expansion requires the binding of thyroid hormones to integrin αvβ3. Convergence of ECM and thyroid hormones on integrin αvβ3 thus appears to be crucial for cortical progenitor proliferation and self-renewal, and hence for normal brain development and the evolutionary expansion of the neocortex.
Denise Stenzel1, Michaela Wilsch-Bräuninger1, Fong Kuan Wong1, Heike Heuer2 and Wieland B. Huttner1,*
+ Author Affiliations
1 Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
2 Leibniz Institute for Age Research / Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
↵* Author for correspondence (firstname.lastname@example.org)
Cortical neurogenesis Integrins Thyroid hormones Mouse
Received July 29, 2013.
Accepted November 28, 2013.
February 15, 2014
Development 141, 795-806.