*Corresponding author: Dr. Lawrence M Agius, 27 “Ballarat” Guzeppe Caruana Street, TalVirtu, Rabat, RBT09, Malta, Europe, Tel: 35621451752, 356-2545-6444, Fax: 356-2545-6449, Email: email@example.com
Neurogenesis arising in the subventricular zone and also subgranular zone in the hippocampus is regulated by two sets of genes, affecting either progenitor neural cells that induce proliferation (eg,, Neurogenins) and differentia- tion neural cells that allow at a subsequent stage the dif- ferentiation of the neural stem cells to maturing neurons.
The specificities of regeneration of neurons constitute a di- mensional re-orientation of substantial cellular resources that are critically interactive with microenvironmental con- ditioning of the neuropil. Surface expansion of the dentate gyrus in multiple sclerosis patients possibly involves an in- flammatory response of the subgranular zone of the hippo- campus. In such terms, the possible important contribu- tions of the extracellular matrix and cell components involve the reconstitution of regions that are initially migratory and later proliferative and differentiating.
The macrophage re-population of neurogenic regions of the adult human brain and spinal cord involves a viable dimen- sional reconstitution that is allied to neuro-trophic factor de- livery and supplement. Indeed, areas that present inhibitory influences to neurogenesis in the adult brain are simply fac- tors of a strictly reparative nature in terms largely implicat- ing astrocytic proliferation and creation of a glial scar. The actively dynamic nature of a focus of injury or of disease in the central nervous system are requisite pre-conditions in the evolution of a multitude of modifying and potentially contributory agents in neuro-injury. Lithium salts are be- lieved to enhance cell proliferation and neurogenesis and to inhibit cell death .
Basic HLH Transcription Factors
The collaborative roles of the circulating blood appear to im- plicate such components as macrophages and platelets oper-
ating in the presence of breakdown of the blood brain barrier and of the blood spinal cord barrier. It is within such context that the emergence of putative regenerative factors operates in essential permissive dynamics of cell reconstitution. Es- trogen 17beta-estradiol influences hippocampal morphology and plasticity and enhances neurogenesis, as seen especially in male rodents experimentally .
Proneural basic helix-loop-helix transcription factors have important roles in binding to DNA and in dimerization with heterologous partners especially co-activators and E-proteins. In such context, HES-1 and HES-5 proteins negatively regulate bHLH transcription factor functions by competing for E-pro- tein binding. Analogous inhibitory roles affecting bHLH tran- scription factors are played by ID (Inhibitor of differentiation) proteins.
Consensus sequences of bHLH factors with glycogen syn- thetase kinase-3 (GSK3) are suggestive for a role of GSK3 phosphorylation in the coupling of extrinsic and intracel- lular pathways involved in bHLH transcriptional activities.
Histone acetylation and histone deacetylation form a self-reg- ulatory series of loops in activating and repressing transcrip- tion of genes, as well-exemplified by anti-epileptic valproic acid which exerts inhibitory effects on histone deacetylases (HDACs) with subsequent enhanced differentiation of adult NSCs to form neurons.
ATP-dependent chromatin remodeling such as Brahma-related gene/Brahma-associated factor (SWI/SNF) in terms of specific complex composition can specifically determine neural stem cell fate specification, including the formation of a neural pro- genitor BAFs (BAF 45a and 53a) to a postmitotic neural BAF (BAF 45 b/c and BAF b).
A novel small double-stranding ncRNA is critically implicated in converting REST/NRSF from a repressor to an activator; the RE1-silencing transcription factor REST otherwise blocks pre- mature neuronal differentiation of neural stem cells.
Neurons have and do present permanent phenotypic attri- butes in the adult CNS.
It is perhaps in such milieu that the progressive replacement of new neurons is strongly dependent on astrocytic cells in particular.
Glial Fibrillary Acidic Protein (GFAP) and S100beta genes are models for understanding astrocytic differentiation mecha- nisms and cytokines in particular (eg IL-6 family of cytokines). The binding of Signal Transducer and Activator of Transcrip- tion (in the JAK-STAT pathway) may activate the gfap promoter
in astrocytic differentiation.
The NOTCH Intracellular domain and RBP-J/k that binds DNA repress gfap expression in self-renewing progenitors. On the other hand, Nuclear Factor1A/B and stem cell leukemia are important in astroglial versus oligodendroglial differentiation.
In such measure, the permissive micro-environment im- plicates the reconstitution of a supporting medium within further conformational realization of subsequent delivery of potentially neurogenic elements as well exemplified by dimensions of possible turnover. Microgravity altered miR- NA possibly affect apoptosis and neurogenesis, as observed in Caenorhabditis elegans. Such cellular turnover is centered within the systems of provision of actively metabolic cell com- ponents such as macrophages and platelets from the circulat- ing blood. Insulin-like growth factor-1 is also known to en- hance neurogenesis and neuronal survival .
Increments of supplied neurotrophic factors would appear operative mediators for the regeneration of a normalized mi- cro-environment that permits the emergence of migrating stem cells and of progenitor cells, as exemplified by the dynam- ics of migration and proliferation of cells from various layers of the subventricular neurogenic layer. In fact, distributional forces create conflicting parameters of regeneration and of re- pair within highly unstable preconditions of possible cell and stromal components. A significant functional role of Myocyte enhancer factor 2a,-c, and –d in cell and non-cell autonomous control of adult hippocampal neurogenesis appears operative that is distinct from its role during development .
NSCs only differentiate to neurons in midgestation, and astro- gliogenesis and oligodendroglial differentiation evolve in late gestational stages, since pluripotentiality of NSCs is not pres- ent in early embryonic stages.
The central role of methylation in gene expression regulation is illustrated by the lack of response of the methylated sequence binding element TTCGGAGAA in the gfap promotor to binding STAT3, with no increased gliogenesis.
An important aspect of mechanistic control is the positive feedback loops as exemplified by methylated gp130-JAK-STAT pathway controlling gliogenic potential of cortical NSCs; cyto- kines are inherently inducers of enhanced induction of their cognate pathway mediators.
Vasculogenesis is a critical dimensional set of parameters that introduces elements of permissiveness of cell migration and proliferation to the injured or diseased foci in such conditions as cortical cortex degeneration.
The performance of inclusive dynamics is correlated with the further promotional effects of cells as well-represented by the glial cells in particular.
Distributional forces would operatively influence and strictly characterize the dynamics of regeneration well beyond the permissive roles of delivery of neurotrophic factors to the dis- eased foci. Inclusive reformations of such regions are simply the permissive aspects of a large multitude of operative path- ways ranging from cell replacement and of matrix reconstitu- tion. The regulatory processes that coordinate stem cell main- tenance can be analyzed mathematically in terms especially of quantifying numbers of cells at different times .
The supply of blood is an essential core phenomenon that dominants as a truly multi-turnover series of system path- ways that primarily appear to target the reconstitution of the extra-cellular matrix. In some manner, the proliferative activi- ties of neurogenic zones are a derivative functionality of a rich blood-supply of such neurogenic zones.
Axonal guidance is a particularly critical phenomenon that ap- pears to precede the process of synaptogenesis. In this regard, parameters of confluence and divergence operate as direction- al cues in the overall process of neurogenesis. In such context, redistribution of chemical mediators would permit the emer- gence of a plethora of phenomenal agent-mediated induction and progression of neuronal potentiality in proliferation and differentiation. Included in such emerging systems there is a series of systemic upsets that paradoxically are supportive of a possible neurogenesis. Development of the prefrontal cortex in its earliest phase in gestation and finally during adolescence incorporate two critical periods of cell proliferation and syn- aptic pruning and may be influenced environmentally in pa- tients who develop schizophrenia .
The central core phenomena that impair possible cell and ma- trix constitution lie within the potentialities of such cells as the circulating macrophages and also the impact of arriving plate- lets to the diseased region of neuronal cell loss. The perfor- mance of further dimensional re-distribution correlates close- ly with the systems of delivery and supply of trophic growth factors and the specific performance of permissive cell/debris replacement. Regular physical activity may increase angio- genesis and neurogenesis and synaptogenesis, including the synthesis of neurotransmitters with increased liberation of neurotrophic factors and the synthesis of enzymatic anti-oxi- dants .
Systems of acquisition are performance-unique in the reali- zation of pathways that generate in their own right the emer- gence of a truly neurogenic potential. Bone marrow-derived mesenchymal stem cells are potential candidates for amelio- rating neurodegenerative states by inducing neurogenesis . Migration tracts represent the actively visible perfor- mance of a cellular and matrix dimensionality that is generally severely lacking in disease foci per se.
Increasing the characterization of neurogenesis is often an at- tribute of targeting that closely follows the ability for creation of migratory tracts and of the appearance of supporting glial cell sub-populations.
The severe diversity of performance dynamics includes the cooperative abilities of a large array of contributing agents as evidenced by the abundance in particular of glial cells on the one hand and of blood-components. Electroconvulsive thera- py appears to mediate, on the other hand, Gadd45b induces proliferation of neural stem cells in the hippocampus .
Performance dynamics are a series of mediating medium for reconstitution of injured foci within the brain and spinal cord in a manner that predominates the global process of replica- tion and differentiation of stem cells and of progenitor cells in particular.
Constitutional performance is a critical component variable that effectively introduces the emergence of neurogenesis in terms of the provision of multi-faceted spectra of cellular convergence and divergence. Forkhead Box O Transcription factors modulate synaptogenesis and adult hippocampal neu- rogenesis, and are also considered possible mechanisms in the development of depression . The further dimensions of dynamic turnover are dominated by a proliferative activity that is inherently differentiating and differential.
In such setting the developmental stages of turnover and of replacement in progression of neurogenesis are central medi- ators in their own right that secondarily characterize a strict stereotype for potential regeneration of injured and diseased CNS tissues. Highly interactive mechanisms of angiogenesis, neurogenesis, oligodendrogenesis, synaptogenesis and axonal sprouting implicate miRNAs and histone deacetylases in post- stroke brain repair, including exosomes’ role in intercellular communication .
Performance processes are inherently operative in the further reconstitution of regions of replacement in terms of the phe- nomena of neuronal migration and replication in neurogene- sis. Indeed, it would appear that the performance dynamics of neurogenesis are per se the instrumental remodeling of pa- rameters that arise initially and later support in highly char- acterized manner the replacement by new neurons. Baicalin induces neuronal differentiation of pluripotent stem cells via modulation of basic helix-loop-helix gene expression .
In such terms, the actual initiation of performance migration and of performance replication of new neurons is an attribute delivered as profile development foci within the human adult brain.
Indeed, neurogenesis is strictly a self-promoted series of events as further supported by the characterized glial stem cells and by the global developmental process of neuronal re-constitution.
It is further to the profile dynamics of such para-developmen- tal parameters that neuronal regeneration further propagates as systems of operative interference on the one hand and of substantial turnover of cells and of variability micro-environ- mental conditioning.
Derivation of system formulae is a parameter of central sig- nificance in the formative processes of new neuronal popula- tions and networks. The performance of migratory tracts and of glial ensheathing pathways are component constitutional parameters invoking the emergence of system biology that in turn strictly correlates with the immediate preceding events of progressive neurogenesis.
Compartmentalization of distinctive influences in turnover appears to signify the global characterization of injury to the brain and spinal cord, as well-evidenced by the breakdown of the blood-brain barrier. Bone-marrow stromal cells appear to enhance neurogenesis via vascular endothelial growth fac- tor-induced or Ki-67-mediated angiogenesis .
In such formulation, delivery forces of directly and indirectly mediating influences would permit the turnover of compo- nents in terms of directional directing of the neurogenic foci as seen in the fetal developing brain. Migratory pathways are semblance pathways that operative developmentally to strictly categorize such development of the brain and spinal cord.
System targeting is itself the permissive element in reconstitu- tion of injured or diseased foci within the central nervous sys- tem. The development of neurogenesis is operative in its own right in terms of the constitutive performance of its characteri- zation. Biologic potential is hence an emergence phenomenon that recruits stem cells and progenitor cells that developmen- tally may be potentially neurogenic as further evidenced in the fetal brain. Sox genes play important roles in neurogenesis as well as sex determination, embryogenesis, oogenesis and lar- val development .
It is the ensuring guidance of migratory neuroblasts that deter- mines the characterization of an essentially permissive series of system attributes as delivered in particular by astrocytes such as radial glial cells.
The roles played by astrocytes in neurogenesis appear to arise as inducing agents, as further formulated by the micro-envi- ronmental pre-conditioning. The toxic micro-environment of the diseased foci of brain and spinal cord injury contributes to the further specialization of the pathology of subsequent neuroblast generation or suppression. Valproic acid induces changes in neural development, neural crest migration, apop- tosis and modulated transcription .
The specificities of the developmental process of neurogene- sis would best be characterized as the permissive milieu for neuronal migration and proliferation of the neurons on the one hand and of the performance modulation of subsequent syn- aptogenesis and of strict neuronal network formulation. Phos- phodiesterases mediate fundamental roles in learning, memo- ry and higher cognitive functions, and phosphodiesterase-4B is important in the hippocampus and constitutes a major Disrupted in Schizophrenia 1 binding partners . In such terms, the inclusive re-characterization of the global process of neurogenesis predominantly dictates operative vasculariza- tion of the foci of neurogenesis in a manner that implicates es- sential permissive performance of neurogenesis per se.
Hence, the dynamics of possible replacement by new neurons is primarily constitutive in strictly formulating a highly per- missive micro-environment for neogenesis. The paradoxical re-definition of new neuronal replacement is primarily as an emergent reversion to pathway of developmental moment.
The significance of further collaborative influence is a neuro- trophic component system in dimensional re-formulation of the possible consequences of injury or disease in neuronal cell loss.
Patterns of apparent autonomy are targeted profiles of recon- stitution within highly permissive re-conditioning of events of a para-developmental nature and progression. Neurogenesis occurs throughout life mainly in the subgranular zone of the hippocampus and the subventricular zone of the lateral ven- tricle; in particular, silencing Sonic hedgehog gene with short hairpin interfering RNA specifically in the mitotic neurons re- duces neurogenesis . The distributional parameters for further characterization appear a much repeated reformula- tion of events as central pathways of migration and replication, as indeed contributed to by radial astrocytes in particular.
Interactive phenomena involve the neuronal network process- ing of existing pathways that further conform to globality of the putative injurious events. Neuropeptide Y, important in regulation of adult hippocampal neurogenesis, ats via intra- cellular nitric oxide in induce increased neural progenitor cell proliferation . Consequential modulations of the neuronal loss area significant performance guided in terms the injury in spectral form within the adjacent brain tissue territories around the foci of injury or disease.
Characters of biologic import are supplemented modulators in further promoting the essential highly permissive pre-condi- tions for further constitutional reformulation of the neurogen- esis. 14-3-3 proteins regulate neural proliferation and differ- entiation of progenitors in the cortex .
A tightly integrated series of sequential events emerge as pro- posed mechanisms that determine fate specification of NSCs, including the suppressed accessibility of binding sites to tran- scription factors, as exemplified by extracellular cues (such as cytokine action) acting on gene promoters secondary to local histone modulation.
The BAF (mammalian SWI/SNF) complexes induce ATP hydro- lysis to change chromatin structure and are found in embry- onic stem cells, neural progenitors and post-mitotic neurons .
tion and is implicated in neurogeneis and hippocampal synap- tic plasticity and also in the modulation of the stress response . Simple juxta-positioning of the trophic and vascular components belie a severely interactive process of neogene- sis as supported principally by astrocytes and other cell-types such as macrophages. Microglia is implicated in modulating neuronal cell death, neurogenesis and synaptic activity .
Sonic hedgehog (Shh) induces expression of OLIG1 and OLIG2
that regulate oligodendrocyte fate-specification.
Inhibition of astrogliogenesis by OLIG2 can also be modulat- ed by sequestration of the coactivator p300 from the action of STAT3 as induced by cytokines.
Induction of ID proteins inhibits OLIG proteins by dimeriza- tion, as also nuclear export of OLIG proteins by Akt. Downreg- ulation of OLIG2 is required for astrogliogenesis.
Performance dynamics are themselves constitutive compo- nents for stereotyped formulas in neogenesis in further signifi- cant dimensions of permissive reconditioning of migrating and proliferating neuroblasts. The astrocytes provide also essen- tial guidance for axonal sprouting and for myelination by dif- ferentiating into various cell subtypes and oligodendrocytes.
Reformulation is a constitutional attribute in regenerative measures such as possible neurogenesis. The developmen- tal paradigm of neogenesis is a potentially highly-informative modulator system in induction and maintenance of such cell- types as stem cells and progenitor cells. The profile setting pathways appear to potentially offer directional parameters that include the targeting of disease foci and of pre-determined systems of modulation in a permissive micro-environment.
and CLEAVED NOTCH + BMP
A proneural factor, neurogenin 1 appears to simultaneously ac- tivate the neurogenic program and inhibits the alternative as- trogliogenic program when specifying neuronal fate, especially via modulation of non-coding RNA epigenetic regulation .
PRONEURAL bHLH Proteins NEUROGENIN1
Performance dynamics of permissive operant influences would therefore be a direct biologic re-characterization of putative neurogenesis, within further fields of subsequent network cre- ation and functionality. The proautophagic proteins Ambra1 and Beclin 1 are highly expressed in the adult subventricular zone and their downregulation induces decreased cell prolifer- ation, increased basal apoptosis and augmented sensitivity to DNA damage . Interleukin-10 suppresses neuroinflamma-
Active Smads Id1 gene, Id3 gene Hes-5 gene
RBP-J/k—Hes-1 gene NEGATIVE HLH PROTEINS. REGULATED NEURAL
DIFFERENTIATION BY bHLH FACTORS.15 IL-6 CYTOKINE
Molecular Pathways of Astrocyte Differentiation.
Gp 130 + BMP Signal + Notch Signal
Cleaved Notch (NICD) + Active Smads + STAT3
JAK-STAT, BMP-Smad, and Notch pathways+ transcription factor NFIA/B
gfap gene Expression
MID-GESTATIONAL Neural Stem Cells
Subventricular astrocyte Transit amplifying progenitor Putative stem cell (Nestin, Dlx2)
(GFAP, Vimentin and Nestin markers)
Migrating neuroblast (PSA-NCAM, Dlx2, Tuj1, Hu)
Immature and mature neurons (DCX, calretinin, Neu N, TH,
Overall Scheme of Neurogenesis
TUJ1—Neuron-specific class III beta-tubulin
DCX—Doublecortin (microtubule-associated protein) PCNA— proliferating nuclear antigen.
PSA-NCAM—polysialylated-neuronal cell adhesion molecule. NeuN—neuronal specific nuclear protein.
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