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Interactive Regulation of Neuronal Development by Hippocampal Stem Cell Niche Populations

2019; Cell Press; Volume: 101; Issue: 1 Linguagem: Inglês

10.1016/j.neuron.2018.12.017

1097-4199

Janel E. Le Belle, Harley I. Kornblum,

Neuroinflammation and Neurodegeneration Mechanisms

Microenvironment cues and cell-to-cell interactions balance stem cell quiescence with proliferation and direct neurogenesis in the adult hippocampal niche. Tang et al. report that hippocampal stem cells release feedback signals that regulate the dendritic complexity and activity of newborn neurons. Microenvironment cues and cell-to-cell interactions balance stem cell quiescence with proliferation and direct neurogenesis in the adult hippocampal niche. Tang et al. report that hippocampal stem cells release feedback signals that regulate the dendritic complexity and activity of newborn neurons. Mammalian neurogenesis is defined as the process that leads to the generation of functional neurons from neural progenitor cells that are ultimately derived from neural stem cells (NSCs). In the adult brain, this only occurs in specialized microenvironments, or "niches," in the forebrain subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, which tightly regulate these cells (Bjornsson et al., 2015Bjornsson C.S. Apostolopoulou M. Tian Y. Temple S. It takes a village: constructing the neurogenic niche.Dev. Cell. 2015; 32: 435-446Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). Different factors and signals regulate the proliferative neurogenic process in the adult niche. Roles in this activity have been described for the vascular and immune systems and the extracellular matrix (ECM) through the release of signaling molecules that act as growth and trophic factors within the niche. Signal cascades derived from Wnt, Sonic Hedgehog, and Notch pathways and intrinsic regulators including p21, PTEN, FoxO3, and p53 are known to regulate stem cell function in the niche through common downstream pathways, including PI3K/AKT and MAPK/ERK. Several different cellular functions are maintained and balanced within the stem cell niche, including quiescence, self-renewal, and differentiation, and we still have much to learn about the mechanisms that underlie the control of this balance. To date, we know the most about the regulation of the stem cell state and less about the signaling related to the newly differentiated neuroblasts and neurons in the niche. It is clear that stem cells and other more differentiated cells within the niche regulate each other and, in doing so, produce the unique niche environment. However, the mechanisms underlying this interactive regulation are still not well understood. In this issue of Neuron, Tang et al., 2018Tang C. Wang M. Wang P. Wang L. Wu Q. Guo W. Neural stem cells behave as a functional niche for the maturation of newborn neurons through the secretion of PTN.Neuron. 2018; (this issue): 32-44PubMed Google Scholar identify an important mechanism for how NSCs initiate and support the development of newborn neurons in the neurogenic niche, which could have wide-ranging applications in endogenous and exogenous brain repair. Physiological or pathological processes, such as learning, exercise, or injury, stimulate proliferation and neurogenesis in the niche through redox, growth factor, or trophic factor mechanisms (Gregorian et al., 2009Gregorian C. Nakashima J. Le Belle J. Ohab J. Kim R. Liu A. Smith K.B. Groszer M. Garcia A.D. Sofroniew M.V. et al.Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.J. Neurosci. 2009; 29: 1874-1886Crossref PubMed Scopus (192) Google Scholar, Gould et al., 1999Gould E. Beylin A. Tanapat P. Reeves A. Shors T.J. Learning enhances adult neurogenesis in the hippocampal formation.Nat. Neurosci. 1999; 2: 260-265Crossref PubMed Scopus (1762) Google Scholar, van Praag et al., 2005van Praag H. Shubert T. Zhao C. Gage F.H. Exercise enhances learning and hippocampal neurogenesis in aged mice.J. Neurosci. 2005; 25: 8680-8685Crossref PubMed Scopus (1563) Google Scholar). New neurons produced in adult stem cell niches can make significant contributions to brain function, such as increasing odor discrimination by the olfactory bulb (Gregorian et al., 2009Gregorian C. Nakashima J. Le Belle J. Ohab J. Kim R. Liu A. Smith K.B. Groszer M. Garcia A.D. Sofroniew M.V. et al.Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.J. Neurosci. 2009; 29: 1874-1886Crossref PubMed Scopus (192) Google Scholar;) and learning and memory in the hippocampus (Gould et al., 1999Gould E. Beylin A. Tanapat P. Reeves A. Shors T.J. Learning enhances adult neurogenesis in the hippocampal formation.Nat. Neurosci. 1999; 2: 260-265Crossref PubMed Scopus (1762) Google Scholar). However, newly born neurons produced in response to injury do not have long-term survival despite their initial integration into the brain at sites away from the niche (Gregorian et al., 2009Gregorian C. Nakashima J. Le Belle J. Ohab J. Kim R. Liu A. Smith K.B. Groszer M. Garcia A.D. Sofroniew M.V. et al.Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.J. Neurosci. 2009; 29: 1874-1886Crossref PubMed Scopus (192) Google Scholar). Thus, a greater understanding of the niche signaling responsible for promoting dendritic outgrowth and maintaining the full integration and long-term survival of neurons produced in the niche would have implications beyond just understanding the basic biology of adult neurogenesis. It would allow appropriate interventions to promote neuronal integration elsewhere in the brain and to intervene in age-related decline in neurogenic niche function. Now, Tang et al., 2018Tang C. Wang M. Wang P. Wang L. Wu Q. Guo W. Neural stem cells behave as a functional niche for the maturation of newborn neurons through the secretion of PTN.Neuron. 2018; (this issue): 32-44PubMed Google Scholar have demonstrated that a specific protein, pleiotrophin (PTN), secreted by the NSCs within the hippocampal SGZ niche is responsible for the maintenance of newborn neuron development in the adult hippocampus. Through a series of knockdown and synaptic tracing experiments, they demonstrated that the main mechanism through which PTN affects newborn neurons in the adult dentate gyrus is by regulating dendritic length and complexity and spine density, leading to functional effects on brain circuit integration and the synaptic activity of the newborn neurons in the hippocampus without directly affecting neuron production or survival. PTN is a secreted protein associated with the extracellular matrix, which is recognized as a significant neuromodulator with multiple neuronal functions during development (Winkler and Yao, 2014Winkler C. Yao S. The midkine family of growth factors: diverse roles in nervous system formation and maintenance.Br. J. Pharmacol. 2014; 171: 905-912Crossref PubMed Scopus (32) Google Scholar) and is involved in hippocampal learning and memory function in the adult brain (González-Castillo et al., 2015González-Castillo C. Ortuño-Sahagún D. Guzmán-Brambila C. Pallàs M. Rojas-Mayorquín A.E. Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus.Front. Cell. Neurosci. 2015; 8: 443Crossref PubMed Scopus (36) Google Scholar). PTN is expressed in several tissues, where its signals are generally related to cell proliferation, growth, and differentiation by acting through different receptors. Tang et al. have identified the downstream signaling mechanism underlying PTN effects within the hippocampal dentate gyrus niche. Specifically, they found that PTN activates AKT signaling to regulate newborn neuron development through the anaplastic lymphoma receptor tyrosine kinase (ALK) receptor. Although several different transmembrane receptors for PTN are known, including ALK, protein tyrosine phosphatase, receptor type Z1 (PTPRZ1), syndecan 3 (SDC3), and chondroitin sulfate proteoglycan 5 (CSPG5) (González-Castillo et al., 2015González-Castillo C. Ortuño-Sahagún D. Guzmán-Brambila C. Pallàs M. Rojas-Mayorquín A.E. Pleiotrophin as a central nervous system neuromodulator, evidences from the hippocampus.Front. Cell. Neurosci. 2015; 8: 443Crossref PubMed Scopus (36) Google Scholar), the authors have identified ALK as the NSC-specific receptor in the dentate gyrus through expression analysis and demonstrations that knockdown and inhibition of ALK function abrogates the PTN effects on new neurons in the niche. The connection between PTN-ALK-AKT signaling has been reported in other systems, but, importantly, Tang et al., have shown how the neural stem cell population is using this signaling to create the niche environment for the maturation of newborn neurons through the secretion of PTN in the adult brain. AKT signaling has a well-established role in maintaining and stimulating neural stem cell self-renewal and survival within the SVZ (Groszer et al., 2006Groszer M. Erickson R. Scripture-Adams D.D. Dougherty J.D. Le Belle J. Zack J.A. Geschwind D.H. Liu X. Kornblum H.I. Wu H. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry.Proc. Natl. Acad. Sci. USA. 2006; 103: 111-116Crossref PubMed Scopus (255) Google Scholar, Gregorian et al., 2009Gregorian C. Nakashima J. Le Belle J. Ohab J. Kim R. Liu A. Smith K.B. Groszer M. Garcia A.D. Sofroniew M.V. et al.Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.J. Neurosci. 2009; 29: 1874-1886Crossref PubMed Scopus (192) Google Scholar, Le Belle et al., 2011Le Belle J.E. Orozco N.M. Paucar A.A. Saxe J.P. Mottahedeh J. Pyle A.D. Wu H. Kornblum H.I. Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner.Cell Stem Cell. 2011; 8: 59-71Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar) and in regulating dendrite complexity of hippocampal DG neurons (Jaworski et al., 2005Jaworski J. Spangler S. Seeburg D.P. Hoogenraad C.C. Sheng M. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway.J. Neurosci. 2005; 25: 11300-11312Crossref PubMed Scopus (467) Google Scholar). However, the use of this common downstream signaling pathway in different cell populations during adult neurogenesis is not fully understood. The authors nicely demonstrate through the selective ablation of the NSCs in the niche that the loss of this population and PTN that they secrete in the niche environment leads to reduced dendritic arborization, spine density, and hippocampal learning ability despite not causing any significant neuron loss. Additionally, the authors demonstrate that the expression level of PTN and the activities of AKT signaling gradually decline in the hippocampus with age but can be rescued through exogenous infusion of PTN which acts during a critical 3-week window to promote dendritic development of newly born neurons. Therefore, their study demonstrates that there is significant potential for exogenous infusion of PTN or pharmacologic activation of AKT signaling to stimulate the full maturation and circuit integration of newborn neurons in the hippocampus or in other non-niche locations as a way of repairing injury or reversing age-related neuronal deficits throughout the brain. Like all good studies, the work of Tang et al. raises just as many questions as it answers and will foster new avenues of research. It will be important to determine what role stem cell-derived pleiotrophin or other similar factors play in other neurogenic niches, such as the adult subventricular zone, as well as in the developing brain. Human neocortical expansion during development has been attributed to neurogenesis by the outer radial glial cell, a dominant primate neurogenic progenitor that is scarce in rodents. Do these cells also influence the development of their progeny using a similar mechanism? Furthermore, these studies and others cited here lead to a highly complex picture of the neurogenic niche as a whole, one that will need to be unraveled to better utilize neural stem and progenitor cells in neural repair strategies. Neural Stem Cells Behave as a Functional Niche for the Maturation of Newborn Neurons through the Secretion of PTNTang et al.NeuronNovember 26, 2018In BriefTang et al. demonstrate that adult NSCs act as a niche for the maturation of newborn neurons through the section of PTN. PTN activates AKT signaling to promote the morphological maturation and synaptic integration of newborn neurons through the ALK receptor. Full-Text PDF Open Archive