V10 Neural stem cells

1. V10 Neural stem cells Various tissue types contains stem cells to replace dead cells. E.g. bone marrow. Typically the number of stem cells is very low. Stem cells need to migrate to their new destination Is this also possible for neural cells? Biological Sequence Analysis

2. Neural stem cells The term "neural stem cell" is used loosely to describe cells that (i) can generate neural tissue or are derived from thenervous system, (ii) have some capacity for self-renewal, and (iii) can give rise to cells other than themselves through asymmetriccell division. Whether stem cells from neural and other tissuesare more defined by their tissue of origin or by their multipotentialityis at present unclear. However, neural stem cells can also bederived from more primitive cells that have the capacity to generateneural stem cells and stem cells of other tissues FH Gage, Science 287, 5457 (2000) Biological Sequence Analysis

3. FH Gage Despite the fact that the human brain is composed of some 100 billion neurons, it’s always been easy to imagine that this number is somehow fixed at birth—that we’re born with our full complement of neurons and then it goes downhill from there. Certainly these neuronal cells will not divide, as other cells do. Not with their enormously extended axons, and tree-like dendrites averaging a thousand synaptic connections each. So how would an adult brain ever add new neurons, and how would it possibly wire them successfully into such an unimaginably complex system? Fred H Gage, Salk Institute Biological Sequence Analysis

4. FH Gage interviewed by ScienceWatch Why has it always been so hard for people to people to believe that the adult brain could give rise to new neurons? First of all, neurons are very complex cells—long branches, receiving hundreds of thousands of connections. The idea that confused people is how something as complex as a neuron could undergo cell division. This idea was not well integrated with the emerging notion that maybe some primitive cells remained and that those were doing the dividing. .. Biological Sequence Analysis

5. FH Gage interviewed by ScienceWatch Why has it always been so hard for people to people to believe that the adult brain could give rise to new neurons? ... The other roadblock was that there were several prominent statements in the literature contending that adult neurogenesis couldn’t happen, because the brain and structures like the hippocampus need to be stable for memory to be stable. If new brain cells were added, that would make it hard to store long-term memories. It was a loose statement, but it resonated with many people ... Biological Sequence Analysis

6. FH Gage interviewed by ScienceWatch How did you, in fact, convince yourself that neurogenesis was going on in adult brains? Among the important elements that helped convince us of this phenomenon were the application of the molecule BrdU—immunocytochemistry, combined with confocal microscopy and quantitative stereology to the measurement of neurogenesis. Biological Sequence Analysis

7. BrdU Bromodeoxyuridine (5-bromo-2-deoxyuridine, BrdU) is a synthetic nucleoside that is an analogue of thymidine. BrdU is commonly used in the detection of proliferating cells in living tissues. BrdU can be incorporated into the newly synthesized DNA of replicating cells (during the S phase of the cell cycle), substituting for thymidine during DNA replication. Antibodies specific for BrdU can then be used to detect the incorporated chemical, thus indicating cells that were actively replicating their DNA. www.wikipedia.org Biological Sequence Analysis

8. FH Gage interviewed by ScienceWatch How did you, in fact, convince yourself that neurogenesis was going on in adult brains? In addition, and equally important, was switching the environment of the mice we studied. We let these animals grow up in little mouse cages as they normally do, and then, when they were adults and were matched for sex, age, genetic background, etc, we took half of them out and put them in a big complex environment and let them stay there for 45 days. Then we just asked simply, are there any changes in the numbers of neurons in the hippocampus? We found this very big effect, and that was the paper we published in Nature in 1997. Biological Sequence Analysis

9. FH Gage interviewed by ScienceWatch So does it occur in the cortex also? So far we haven’t seen it under normal conditions. It’s been claimed in other areas as well, and we’re not saying that it doesn’t happen at very, very low frequency or under damaged conditions, but we haven’t seen it. I’m still open to the idea, however, since we’ve shown that even cells from the spinal cord can be induced to become neurons after being cultured and transplanted to the hippocampus, and there’s no neurogenesis going on naturally in the spinal cord. So our conclusion is that there are neural stem cells all over the brain and in the spinal cord, but they don’t give to rise to neurons under normal conditions because the local environment doesn’t provide them with the appropriate cues. Biological Sequence Analysis

10. FH Gage interviewed by ScienceWatch So what role does neurogenesis play in the brain, and why in the hippocampus in particular? That’s an open question. Why has this part of the brain reserved the capacity to generate neurons? It’s not a ubiquitous phenomenon. So why does it happen in this brain structure? We don’t know yet, although I think it will be resolved in the next couple of years. ... Biological Sequence Analysis

11. FH Gage interviewed by ScienceWatch So what role does neurogenesis play in the brain, and why in the hippocampus in particular? ... In order to know what role neurogenesis plays in hippocampal function or system-wide function, we have to know what role the hippocampus is playing. We’re not able to understand neurogenesis itself, without understanding this structure in which it occurs. So this is a very exciting time for developing model systems—knockout technologies, for instance. Every day in the literature, there’s another neurogenesis article published. There are some really smart people getting into this field, and they’re discovering some wonderful things. Biological Sequence Analysis

12. Neural stem cells Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1992, Reynolds and Weiss were the first to isolate neural progenitor and stem cells from adult mice brain tissue. Since then, neural progenitor and stem cells have been isolated from various areas of the adult brain and from various species including human. www.wikipedia.org Biological Sequence Analysis

13. Role of mitogens Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens for neural progenitor and stem cells in vitro, though other factors synthesized by the neural progenitor and stem cells in culture are required for their growth. It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined. www.wikipedia.org Biological Sequence Analysis

14. Neural stem cells An illustration proposing the classes of mammalian stem cells that can give rise to neurons, presented as a hierarchy beginning with the most primitive and multipotent stem cell and progressing to the most restricted. The restrictions of fate at each step and examples of sites in the body where they can be obtained are also presented. As our understanding of the true potential and nature of stem cells is still unfolding, modifications will clearly be added. E.g., the small arrows pointing up suggest the potential, although not well documented, dedifferentiation of the more restricted cell below. FH Gage, Science 287, 5457 (2000) Biological Sequence Analysis

15. TLX Nuclear receptors are ligand-dependent transcription factors that regulate the expression of genes critical for a variety of biological processes, including development, growth, and differentiation. TLX is an orphan nuclear receptor that plays an important role in vertebrate brain functions. TLX is an essential regulator of neural stem cell proliferation and self-renewal in the adult brain. PNAS 104, 15282 (2007) Biological Sequence Analysis

16. TLX Expression of TLX in the mouse - starts at embryonic day 8 (E8), - peaks at E13.5 and - decreases by E16, with barely detectable levels at birth. TLX expression increases again after birth and is high in the adult brain. Although TLX-null mice appear grossly normal at birth, mature mice manifest a rapid retinopathy with reduced cerebral hemispheres. TLX could act by controlling the expression of a network of downstream target genets to establish the undifferentiated and self-renewable state of neural stem cells. PNAS 104, 15282 (2007) Biological Sequence Analysis

17. Roles of TLX Removal of TLX from the adult mouse brain resulted in a reduction of stem cell proliferation and spatial learning Nature 451, 1004 (2008) Biological Sequence Analysis

18. Roles of TLX PNAS 104, 15282 (2007) Biological Sequence Analysis

19. Canonical miRNA biogenesis The Canonical miRNA biogenesis pathway. pri-miRNAs are transcribed primarily as RNA pol II transcripts. The pri-miRNAs are processed co-transcriptionally by the Microprocessor (Drosha/Dgcr8). Following Microprocessor cleavage, Exportin-5 transports the pre-miRNA hairpin into the cytoplasm. There, the pre-miRNA is cleaved by Dicer, resulting in a miRNA/miRNA* complex. With the help of TRBP, the mature miRNA is loaded into the Argonaute subunit of the silencing complex. This complex then goes onto silence target mRNAs post-transcriptionally by translational inhibition and/or transcript destablization. www.stembook.org√ Biological Sequence Analysis

20. Non-canonical miRNA biogenesis The Non-canonical miRNA biogenesis pathway. Mirtrons are short introns which form pre-miRNA hairpins following splicing and debranching of the transcript. The endogenous shRNAs are directly transcribed as pre-miRNA hairpins. www.stembook.org√ Biological Sequence Analysis