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Developmental Biology - Brain Cells

Unblocking Stem Cell Division In Old Brains

Controlling cell proliferation using gene regulator Id4 might potentially counteract brain aging...

Scientists at the University of Basel, Switzerland, investigating brain stem cells in mice, have discovered a key mechanism to cell proliferation. Their research results are published in Cell Reports, and may be useful in treating neurodegenerative diseases in human brains.

Whether stem cells also occur in the human brain has long been a controversial subject. Today, it is considered certain the brain forms new neurons throughout a lifetime but, only in specialized regions of the brain called niches. Niches regulate differentiation signals which indicate when stem cells need to divide. However, with increasing age, stem cells divide less frequently and brain stem cells transition into a "quiescent" or dormant state.

Hyperactive signaling pathway inhibits cell division

So far, it's been unclear why stem cells in the adult and old brain fall into this state of "quiescence" or dormancy. Now a research team led by Prof. Verdon Taylor, Department of Biomedicine, University of Basel, has just discovered which factors block stem cells from dividing. They began by investigating the Notch signaling pathway in more detail. This pathway is central in regulating stem cell activity in the brain.

Their study shows the Notch2 signaling pathway controls expression or function of a specific transcription regulator called Id4. Once expressed, Id4 stops division of stem cells, blocking production of new neurons in the hippocampus of an adult brain. However, Notch2 signals maintain high levels of Id4 in some neural stem cells, which explains why these stem cells also increasingly enter dormancy in adult and geriatric brains.
As the brain ages, the Notch2-Id4 pathway enters a state of hyperactivity, presenting a strong molecular brake inhibiting stem cell activation and production of neurons. Conversely, inactivation of this pathway releases the brake enabling production of new neurons - even in the brain of geriatric mice.

Reversible resting state

Test results show that stem cells in the mammalian brain are in a reversible resting state regulated by signals and factors within brain niches. By manipulating these signaling pathways, the production of new nerve cells can be specifically stimulated. This is important information on the basic mechanisms of neurogenesis in the adult mouse brain.
As the Notch signaling pathway occurs in most organisms, researchers hope their findings are transferrable to humans. If so, brain damage caused by degenerative and neuropsychiatric diseases could be repaired in the future.

Notch2 regulates Id4 and cell-cycle genes in hippocampal NSCs
Id4 blocks hippocampal NSC entry into cell cycle
Id4 promotes astrocytic differentiation of hippocampal NSCs
NSC activation and neuronal differentiation can be uncoupled

Neural stem cells (NSCs) in the adult mouse hippocampal dentate gyrus (DG) are mostly quiescent, and only a few are in cell cycle at any point in time. DG NSCs become increasingly dormant with age and enter mitosis less frequently, which impinges on neurogenesis. How NSC inactivity is maintained is largely unknown. Here, we found that Id4 is a downstream target of Notch2 signaling and maintains DG NSC quiescence by blocking cell-cycle entry. Id4 expression is sufficient to promote DG NSC quiescence and Id4 knockdown rescues Notch2-induced inhibition of NSC proliferation. Id4 deletion activates NSC proliferation in the DG without evoking neuron generation, and overexpression increases NSC maintenance while promoting astrogliogenesis at the expense of neurogenesis. Together, our findings indicate that Id4 is a major effector of Notch2 signaling in NSCs and a Notch2-Id4 axis promotes NSC quiescence in the adult DG, uncoupling NSC activation from neuronal differentiation.

Runrui Zhang, Marcelo Boareto, Anna Engler, Angeliki Louvi, Claudio Giachino, Dagmar Iber and Verdon Taylor.

The authors would like to thank Dr. Jan S. Tchorz for providing Rosa26R-CAG::floxed-STOP-Notch2ICD mice, Dr. Spyros Artavanis-Tsakonas for providing Notch2::CreERT2-SAT Rosa26R-CAG::tdTomato mice, Drs. Kirsten Obernier and Arturo Alvarez-Buylla for providing the Adeno-gfap::Cre virus, Dr. H. R. MacDonald for providing the Notch1 and Notch2 antibodies, and Fred Sablitzky for providing the Id4 cDNA clone. We thank the members of the Taylor lab for critical reading and correction of the manuscript, and Frank Sager for excellent technical assistance. We thank Dr. Christian Beisel of the Genomics Facility Basel of D-BSSE for NGS RNA sequencing, and the animal core facility of the University of Basel and the BioOptics Facility of the Department of Biomedicine for support. We thank Francois Guillemot, Noelia Urban, and Isabelle Blomfield for sharing unpublished data and Jane E. Visvader for providing the Id4lox/lox mice. This work was supported by the SystemsX.ch project NeuroStemX ( 51RT-0_145728 to V.T.), the Swiss National Science Foundation ( 310030_143767 and 31003A_162609 to V.T.), the University of Basel , and the Forschungsfonds of the University of Basel (R.Z.).

Author Contributions
The authors declare no competing interests.

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Nov 7 2019   Fetal Timeline   Maternal Timeline   News  

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At one point in time, whether stem cells existed in the human brain was controversial. Today, it is certain the brain forms new neurons throughout life. But, stem cells are restricted to specialized brain niches. Key signals regulate their self-renewal and differentiation. With age, they become increasingly inactive and divide less frequently transitioning into a "quiescent" or dormant state.

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