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Blood vessels control brain growth

Blood vessels play a vital role in stem cell reproduction, enabling the brain to grow and develop in the womb, reveals new research in mice.

The study shows that blood vessels can increase the number of neural stem cells inside a living organism. This could be important for the design of stem cell-based therapies that aim to regenerate diseased or damaged parts of the nervous system.

The work is published in the Proceedings of the National Academy of Sciences or PNAS.

In the developing brain, new neurons are produced by neural stem cells in 'neurogenic' areas of the brain.

Here they have to be instructed when and how often they should divide or what type of cell progeny they should produce. Until now, however, the signals responsible for these instructions were elusive.

Explains lead author Mathew Tata, University College London (UCL) Institute of Ophthalmology: "We found that blood vessels play a vital role in telling neural stem cells when and how to reproduce. We examined neural stem cell behaviour in the brainstem of mice lacking the blood vessel protein NRP1, because this part of the brain is particularly important to control fundamental processes such as breathing and heart rate.

"Preventing blood vessel growth in the neurogenic areas of the brainstem interfered with normal neuron production, causing neural stem cells to lose their ability to reproduce. As a result, stem cells disappeared from the brainstem before its growth was complete.

"Therefore, mice lacking NRP1 ended up with smaller brainstems."

The research provides the first evidence that blood vessels are not only important for delivering blood to the developing brain, but also play an important role in stem cell signalling.

"Blood vessels are best known for their important function in supplying oxygen and nutrients to the brain.

"However, the most intriguing finding of this study was that blood vessels did not regulate neural stem cell behaviour in the brainstem simply through their role in brain oxygenation or keeping brain tissue healthy.

"We found that blood vessels also provide important signals that allow stem cells to reproduce for a longer period of time — before they permanently become nerve cells that cannot multiply."

Christiana Ruhrberg PhD, Developmental Biology, Cell Biology, Institute of Ophthalmology, University College London, London, England, and senior author.

Neural progenitor cells (NPCs) proliferate to generate precursors for new neurons. To sustain this process, NPCs balance self-renewal with the generation of progeny committed to neuronal differentiation. In the adult mammalian brain, blood vessels and vessel-derived factors help regulate this balance by modulating NPC proliferation and quiescence, independently of vascular roles in providing oxygen and nutrients. In contrast, it has been proposed that vasculature regulates NPC behavior in the developing forebrain by alleviating tissue hypoxia. We show here that germinal zone vasculature in the embryonic hindbrain regulates the balance of NPC self-renewal with neuron production, independently of roles in tissue oxygenation. Information on how blood vessels regulate neurogenesis may aid in the design of therapies for brain regeneration in injury and disease.

In the adult rodent brain, new neurons are born in two germinal regions that are associated with blood vessels, and blood vessels and vessel-derived factors are thought to regulate the activity of adult neural stem cells. Recently, it has been proposed that a vascular niche also regulates prenatal neurogenesis. Here we identify the mouse embryo hindbrain as a powerful model to study embryonic neurogenesis and define the relationship between neural progenitor cell (NPC) behavior and vessel growth. Using this model, we show that a subventricular vascular plexus (SVP) extends through a hindbrain germinal zone populated by NPCs whose peak mitotic activity follows a surge in SVP growth. Hindbrains genetically defective in SVP formation owing to constitutive NRP1 loss showed a premature decline in both NPC activity and hindbrain growth downstream of precocious cell cycle exit, premature neuronal differentiation, and abnormal mitosis patterns. Defective regulation of NPC activity was not observed in mice lacking NRP1 expression by NPCs, but instead in mice lacking NRP1 selectively in endothelial cells, yet was independent of vascular roles in hindbrain oxygenation. Therefore, germinal zone vascularization sustains NPC proliferation in the prenatal brain.

Search terms: blood vessel neural progenitor neurogenesis hindbrain NRP1

Funded by the Wellcome Trust, for more information: https://wellcome.ac.uk/what-we-do

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Nov 11, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Neurogenesis takes place in the subventricular zone (SVZ) which forms the lining of the
lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus area.
The SVZ is where neuroblasts are formed, and then migrate via the rostral migratory stream
to the olfactory bulb.

Image Credit:
Laurie O'Keefe The Scientist


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