Biomedical subjects

S Gokhan

Publications and source records attributed to S Gokhan.

6 recordsLinked to original sources

PubMed2001

Developmental mechanisms in the pathogenesis of neurodegenerative diseases.

Cellular genes that are mutated in neurodegenerative diseases code for proteins that are expressed throughout neural development. Genetic analysis suggests that these genes are essential for a broad range of normal neurodevelopmental processes. The proteins they code for interact with numerous other cellular proteins that are components of signaling pathways involved in patterning of the neural tube and in regional specification of neuronal subtypes. Further, pathogenetic mutations of these genes can cause progressive, sublethal alterations in the cellular homeostasis of evolving regional neuronal subpopulations, culminating in late-onset cell death. Therefore, as a consequence of the disease mutations, targeted cell populations may retain molecular traces of abnormal interactions with disease-associated proteins by exhibiting changes in a spectrum of normal cellular functions and enhanced vulnerability to a host of environmental stressors. These observations suggest that the normal functions of these disease-associated proteins are to ensure the fidelity and integration of developmental events associated with the progressive elaboration of neuronal subtypes as well as the maintenance of mature neuronal populations during adult life. The ability to identify alterations within vulnerable neuronal precursors present in pre-symptomatic individuals prior to the onset of irrevocable cellular injury may help foster the development of effective therapeutic interventions using evolving pharmacologic, gene and stem cell technologies.

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PubMed2000

Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat.

Genes associated with neurodegenerative diseases are normally expressed throughout neural development and are essential for the elaboration and maintenance of neuronal subpopulations. Disease-causing mutations can compromise defined subsets of these neural specification events in subtle ways that initially lead to impairments in the cellular homeostasis of evolving regional neuronal subpopulations, and adult-onset cell death from normally non-lethal environmental stressors. Neurodegenerative diseases may, therefore, represent an emerging class of developmental disorders characterized by novel biological responses to subthreshold neurodevelopmental abnormalities that impair targeted neuronal biosynthetic pathways without causing obvious developmental deficits. This developmental model of pathogenesis predicts that it will soon be possible to identify these dysfunctional pathways prior to the occurrence of irreversible cellular injury, and to successfully intervene using innovative neuroprotective and neural regenerative strategies.

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PubMed2000

Developmental changes in progenitor cell responsiveness to bone morphogenetic proteins differentially modulate progressive CNS lineage fate.

Although multipotent progenitor cells capable of generating neurons, astrocytes and oligodendrocytes are present within the germinal zones of the brain throughout embryonic, postnatal and adult life, the different neural cell types are generated within discrete temporospatial developmental windows. This might suggest that multipotent progenitor cells encounter different signals during each developmental stage, thus accounting for separate waves of lineage commitment and cellular differentiation. This study demonstrates, however, that progenitor cell responses to the same class of signals, the bone morphogenetic proteins (BMPs), change during ontogeny, and that these same signals may thus initiate progenitor cell elaboration of several different lineages. BMPs promote cell death and inhibit the proliferation of early (embryonic day 13, E13) ventricular zone progenitor cells. At later embryonic (E16) stages of cerebral cortical development, BMPs exhibit a concentration-dependent dissociation of cellular actions, with either enhancement of neuronal and astroglial elaboration (at 1-10 ng/ml) or potentiation of cell death (at 100 ng/ml). Finally, during the period of perinatal cortical gliogenesis, BMPs enhance astroglial lineage elaboration. By contrast, oligodendroglial lineage elaboration is inhibited by the BMPs at all stages. Further, application of the BMP antagonist noggin to cultured progenitors promotes the generation of oligodendrocytes, indicating that endogenous BMP signaling can actively suppress oligodendrogliogenesis. These observations suggest that developmental changes in neural progenitor cell responsiveness to the BMPs may represent a novel mechanism for orchestrating context-specific cellular events such as lineage elaboration and cellular viability.

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PubMed1999

Postnatal cerebral cortical multipotent progenitors: regulatory mechanisms and potential role in the development of novel neural regenerative strategies.

In the developing postnatal cerebral cortex, protracted generation of glia and neurons occurs and precise matching of local cell types is needed for the functional organization of regional microdomains characteristic of complex CNS tissues. Recent studies have suggested that multipotent progenitors play an important role in neural lineage elaboration during neurogenesis and gliogenesis after migration from paramedian generative zones. The presence of a separate reservoir of cerebral cortical multipotent cells under strict local environmental regulation would provide an appropriate mechanism for terminal developmental sculpting and for reconstitution of regional cellular pools after injury. We have isolated distinct pools of EGF- and bFGF-responsive multipotent progenitors from the postnatal mammalian cerebral cortex independent of the subventricular zone. These progenitor populations are under tight environmental regulation by specific hierarchies of cytokine subclasses that program the progressive elaboration of intermediate lineage-restricted progenitors and differentiated type I and II astrocytes, myelinating oligodendrocytes and neuronal subtypes that express specific neuromodulatory proteins. Neural lineage development from these cortical multipotent progenitors is a graded developmental process involving sequential induction of specific cytokine receptors, acquisition of factor responsiveness and complex lineage interdependence. The cortical multipotent progenitor pathways program the elaboration of neural lineage species with distinct cellular response properties when compared with analogous species derived from subventricular zone progenitors, indicating that the cortical multipotent cells contribute to the establishment of lineage diversity within the developing cortical cortex. In addition, the cortical multipotent cells generate dynamic intermediate progenitor pools that utilize temporally-coded environmental cues to alter neural fate decisions. These cumulative observations suggest that postnatal cerebral cortical multipotent cells represent a novel set of progenitor pathways necessary for normal mammalian cortical maturation, and may have important implications for our understanding of a wide variety of neuropathological conditions and for the development of more effective regenerative strategies to combat these pervasive neurological disorders.

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PubMed1998

Isolation and developmental characterization of cerebral cortical multipotent progenitors.

Multipotent neural progenitor species present within developing and adult periventricular generative zones can give rise to all of the major cellular elements of the brain. Although lineage specification during development has been thought to be restricted to these generative zones, we have utilized quantitative immunoselection techniques to isolate an enriched population of multipotent neural progenitor cells that express polysialylated neural cell adhesion molecule (PSA-NCAM) from postnatal day 2 cerebral cortex independent of generative zones. This population of cerebral cortical progenitor cells exhibited robust proliferation in response to epidermal growth factor and subsequently gave rise to clonally derived neurons, astrocytes, and oligodendrocytes. Quantitative regional analysis further demonstrated that while the multipotent cells derived from the cerebral cortex uniformly expressed PSA-NCAM, multipotent cells derived from generative zones contained equal proportions of PSA-NCAM-positive and -negative multipotent progenitor cells. The generation of individual cellular lineages from cortical multipotent progenitors could be enhanced by specific cytokines that are expressed within the cerebral cortex. Further, while oligodendroglial progenitor cells derived from cortical multipotent progenitors exhibited responsiveness to platelet-derived growth factor (PDGF) and neurotrophin-3 (NT-3), primary cultures of cortical oligodendroglial progenitors were responsive to PDGF but not to NT-3. These observations suggest that in addition to glial progenitors that commit to a specific lineage prior to migration from generative zones, there is within the cerebral cortex a separate pool of multipotent cells that are capable of generating mature glial progeny in response to specific environmental cues. Therapeutic interventions aimed at differentiation of endogenous cerebral pools of multipotent progenitors may provide a novel strategy for amelioration of the sequelae of environmental and genetic insults to the postnatal cerebrum.

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PubMed1998

Differentiation of oligodendroglial progenitors derived from cortical multipotent cells requires extrinsic signals including activation of gp130/LIFbeta receptors.

We have previously isolated epidermal growth factor (EGF)-responsive multipotent progenitor cells from the early postnatal rodent cerebral cortex independent of generative zones. In this study we have examined the mechanisms regulating the generation of differentiated oligodendrocytes (OLs) from these multipotent cells. Although cultures of primary cortical OL progenitor cells propagated at clonal density spontaneously gave rise to differentiated OLs in defined medium, cultures of multipotent progenitors isolated from identical regions supported the elaboration of OL progenitors but not differentiated OLs. These observations indicate that the terminal maturation of OL progenitors derived from multipotent cells is dependent on signals present within the cellular environment. Application of cytokines such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), or neurotrophin 3 (NT3) to clonal density cultures of cortical multipotent progenitors increased the proportion of OL progenitors but failed to support the generation of differentiated OLs. By contrast, application of factors that activate gp130/leukemia inhibitory factor beta (LIFbeta) heterodimeric receptors, such as ciliary neurotrophic factor (CNTF), activated signal transducers and activators of transcription-3 in these OL progenitor cells and promoted the generation of differentiated OLs. Clonal analysis also demonstrated that CNTF directly targets OL progenitors derived from the multipotent cells. These observations suggest that two distinct progenitor cell pathways contribute to the generation of differentiated OLs during postnatal cortical gliogenesis. Although oligodendroglial maturation of classical OL progenitor cells is driven by cell autonomous mechanisms, our findings demonstrate that the generation of differentiated OLs from cortical multipotent progenitor cells is dependent on environmental cues, including activation of gp130/LIFbeta receptors.

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