Harun N Noristani | Temple University (original) (raw)

Papers by Harun N Noristani

Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal c... more Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity. We analyzed molecular alterations in microglia at several time-points after different SCI severities using RNA-sequencing. We demonstrate that activation of microglia is time-dependent post-injury but is independent of lesion severity. Early transcriptomic response of microglia after SCI involves proliferation and neuroprotection, which is then switched to neuroinflammation at later stages. Moreover, SCI induces an autologous microglial expression of astrocytic markers with over 6% of microglia expressing glial fibrillary acidic protein and vimentin from as early as 72 h post-lesion and up to 6 weeks after injury. We also identified the potential involvement of DNA damage and in particular tumor suppressor gene breast cancer susceptibility gene 1 (Brca1) in microglia after SCI. Finally, we established that BRCA1 protein is specifically expressed in non-human primate spinal microglia and is upregulated after SCI. Our data provide the first transcriptomic analysis of microglia at multiple stages after different SCI severities. Injury-induced microglia expression of astrocytic markers at RNA and protein levels demonstrates novel insights into microglia plasticity. Finally, increased microglia expression of BRCA1 in rodents and non-human primate model of SCI, suggests the involvement of oncogenic proteins after CNS lesion.

Spinal cord injury (SCI) triggers pronounced astrocyte reactivity (astrogliosis) including astrog... more Spinal cord injury (SCI) triggers pronounced astrocyte reactivity (astrogliosis) including astroglial proliferation and migration toward the injury site participating to the formation of a glial scar. Since the mid-20 th century, SCI-induced astrogliosis was mainly regarded as detrimental for successful axonal regeneration. However, more recent studies have shown astrogliosis as a multifactorial phenomenon involving specific morphological, molecular and functional alterations in astrocytes that can also exert beneficial effects . It was suggested, although not proven, that SCI-induced astrogliosis depends on multiple factors such as time after lesion, injury severity and distance to the lesion site. In a recent study we had attempted to uncover the molecular involvement of astrocytes after SCI by studying their transcriptomic alterations at different stages after moderate and severe lesions .

Background: Neurons have intrinsic capability to regenerate after lesion, though not spontaneousl... more Background: Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate. Methods: We analyzed molecular changes in astrocytes at multiple stages after two SCI severities using cell-specific transcriptomic analyses. Results: We demonstrate that astrocyte response after injury depends on both time after injury and lesion severity. We then establish that injury induces an autologous astroglial transdifferentiation where over 10 % of astrocytes express classical neuronal progenitor markers including βIII-tubulin and doublecortin with typical immature neuronal morphology. Lineage tracing confirmed that the origin of these astrocytes is resident mature, rather than newly formed astrocytes. Astrocyte-derived neuronal progenitors subsequently express GABAergic, but not glutamatergic-specific markers. Furthermore, we have identified the neural stem cell marker fibroblast growth factor receptor 4 (Fgfr4) as a potential autologous modulator of astrocytic transdifferentiation following SCI. Finally, we establish that astroglial transdifferentiation into neuronal progenitors starts as early as 72 h and continues to a lower degrees up to 6 weeks post-lesion. Conclusion: We thus demonstrate for the first time autologous injury-induced astroglial conversion towards neuronal lineage that may represent a therapeutic strategy to replace neuronal loss and improve functional outcomes after central nervous system injury.

Frontiers in Neuroanatomy, 2015

Spinal cord injury (SCI) is a debilitating neuropathology with no effective treatment. Magnetic r... more Spinal cord injury (SCI) is a debilitating neuropathology with no effective treatment. Magnetic resonance imaging (MRI) technology is the only method used to assess the impact of an injury on the structure and function of the human spinal cord. Moreover, in pre-clinical SCI research, MRI is a non-invasive method with great translational potential since it provides relevant longitudinal assessment of anatomical and structural alterations induced by an injury. It is only recently that MRI techniques have been effectively used for the follow-up of SCI in rodents. However, the vast majority of these studies have been carried out on rats and when conducted in mice, the contusion injury model was predominantly chosen. Due to the remarkable potential of transgenic mice for studying the pathophysiology of SCI, we examined the use of both in and ex vivo 1 H-MRI (9.4 T) in two severities of the mouse SCI (hemisection and over-hemisection) and documented their correlation with histological assessments. We demonstrated that a clear distinction between the two injury severities is possible using in and ex vivo 1 H-MRI and that ex vivo MR images closely correlate with histology. Moreover, tissue modifications at a remote location from the lesion epicenter were identified by conventional ex vivo MRI analysis. Therefore, in vivo MRI has the potential to accurately identify in mice the progression of tissue alterations induced by SCI and is successfully implemented by ex vivo MRI examination. This combination of in and ex vivo MRI follow-up associated with histopathological assessment provides a valuable approach for further studies intended to evaluate therapeutic strategies on SCI.

Alzheimer's & Dementia, 2010

neurotransmitter in learning and memory processes. Alterations in 5-HT neurotransmission have bee... more neurotransmitter in learning and memory processes. Alterations in 5-HT neurotransmission have been recently implicated in AD, however, it is not clear how hippocampal 5-HT innervation is modified. Methods: We studied the hippocampal 5-HT input by analyzing (i) the expression, density and distribution of serotonin transporter immunoreactive fibres (SERT-IRF); (ii) the specific morphological characteristics of serotonergic fibres and their relation to amyloid plaques; (iii) the distribution and synaptic connectivity of serotonergic terminals and unmyelinated axons (SERT-Te/Ax) and (iv) the total number of serotonin neurones within the raphe nuclei in the triple transgenic mouse model of Alzheimer's disease (3xTg-AD). We used quantitative light and electron microscopy immunohistochemistry to analyze the differences between 3xTg-AD and non-transgenic animals (non-Tg) at different ages (3, 6, 9, 12 and 18 months). Results: 3xTg-AD showed a significant increase in SERT-IRF density in the hippocampus in a subfield, strata and age specific manner. The increase in SERT-IRF was specific to the CA1 stratum lacunosum moleculare. Increase in SERT-IRF in 3xTg-AD was observed at 3 months (61%) and at 18 months (74%) when compared to non-Tg. Increased SERT-IRF density was more pronounced adjacent to amyloid plaques. Ultrastructural studies also revealed that the 3xTg-AD animals have an specific concomitant increase of SERT-Te/Ax in the CA1. This Increase in SERT-Te/Ax in transgenic animals was observed also at 3 months (146 %) and at 18 months (153 %) of non-Tg values. In addition, SERT-Te/Ax had a significant increased surface area these ages (67% and 50% respectively). However, no changes were found in the total number of raphe serotonin neurones at any age. Conclusions: Our results indicate that triple transgenic mice display increased SERT-IRF sprouting and increased SERT-Te density which may account for imbalanced serotonergic neurotransmission associated with Alzheimer's disease cognitive impairment.

Aging Cell, 2012

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs mnesic functions... more Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs mnesic functions. The histopathology of the disease is manifested by the accumulation of intracellular bamyloid (Ab) and subsequent formation of neuritic plaques as well as the presence neurofibrillary tangles in specific brain regions associated with learning and memory including the hippocampus. Here, we analysed the effect of chronic (1 month) food diets containing low (LTrP), normal (NTrP) and high tryptophan (HTrP), 0.04, 0.20 and 0.40 g ⁄ 100 g, respectively, on CA1 serotonin transporter (SERT) fibre density, intraneuronal Ab deposition and total number of serotonergic (5-HT) neurons in an AD triple transgenic (3xTg-AD) mouse model. Nontransgenic (non-Tg) animals fed with HTrP displayed increased SERT fibre density in CA1 (35%) and in stratum lacunosum moleculare (S.Mol) (48%) compared to LTrP diet. Transgenic animals showed increased SERT fibre density in CA1 S.Mol compared to diet-matched non-Tg irrespective of dietary tryptophan content (104% for LTrP, 74% for NTrP and 35% for HTrP); no differences were observed in the total number of 5-HT neurons neither in the dorsal nor in the median raphe nuclei. However, and more relevant to AD, HTrP diet reduced intraneuronal Ab density (by a 17%) in transgenic animals compared to transgenic animals fed with NTrP diet. Our results show that increased dietary TrP intake reduces intraneuronal Ab load in the 3xTg-AD mouse model of AD, suggesting that enhanced TrP intake and in consequence a potential increase in 5-HT neurotransmission may be effective in reducing plaque pathology in AD.

Background: There is growing evidence that microglia are key players in the pathological process ... more Background: There is growing evidence that microglia are key players in the pathological process of amyotrophic lateral sclerosis (ALS). It is suggested that microglia have a dual role in motoneurone degeneration through the release of both neuroprotective and neurotoxic factors. Results: To identify candidate genes that may be involved in ALS pathology we have analysed at early symptomatic age (P90), the molecular signature of microglia from the lumbar region of the spinal cord of hSOD1 G93A mice, the most widely used animal model of ALS. We first identified unique hSOD1 G93A microglia transcriptomic profile that, in addition to more classical processes such as chemotaxis and immune response, pointed toward the potential involvement of the tumour suppressor gene breast cancer susceptibility gene 1 (Brca1). Secondly, comparison with our previous data on hSOD1 G93A motoneurone gene profile substantiated the putative contribution of Brca1 in ALS. Finally, we established that Brca1 protein is specifically expressed in human spinal microglia and is up-regulated in ALS patients.

Cell Death and Disease, 2011

Alzheimer's disease (AD) is a neurodegenerative pathology that deteriorates mnesic functions and ... more Alzheimer's disease (AD) is a neurodegenerative pathology that deteriorates mnesic functions and associated brain regions including the hippocampus. Serotonin (5-HT) has an important role in cognition. We recently demonstrated an increase in 5-HT transporter (SERT) fibre density in the hippocampal CA1 in an AD triple transgenic mouse model (3xTg-AD). Here, we analyse the ultrastructural localisation, distribution and numerical density (N v ) of hippocampal SERT axons (SERT-Ax) and terminals (SERT-Te) and their relationship with SERT fibre sprouting and altered synaptic N v in 3xTg-AD compared with non-transgenic control mice. 3xTg-AD animals showed a significant increase in SERT-Te N v in CA1 at both, 3 (95%) and 18 months of age (144%), being restricted to the CA1 stratum moleculare (S. Mol; 227% at 3 and 180% at 18 months). 3xTg-AD animals also exhibit reduced N v of perforated axospinous synapses (PS) in CA1 S. Mol (56% at 3 and 52% at 18 months). No changes were observed in the N v of symmetric and asymmetrical synapses or SERT-Ax. Our results suggest that concomitant SERT-Te N v increase and PS reduction in 3xTg-AD mice may act as a compensatory mechanism maintaining synaptic efficacy as a response to the AD cognitive impairment.

Alzheimer's & Dementia, 2010

or saline as a placebo for six weeks (daily i.p. 50 nmol/injection) to 7-8 months 3xTgAD mice and... more or saline as a placebo for six weeks (daily i.p. 50 nmol/injection) to 7-8 months 3xTgAD mice and WT control animals. After four weeks of treatment, general behavior and learning and memory function were evaluated. At the end of the treatment, animals were sacrificed, brains dissected, and the effects of treatment with Peptide 6 on neurogenesis and neuronal plasticity studied by immunohistochemistry. Results: Treatment with Peptide 6 did not induce weight loss or other side effects observed previously with CNTF. Instead it restored 3xTgAD mice impairments in object discrimination task as well as in spatial reference memory task. This treatment also restored neurogenesis alterations in 3xTgAD mice dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and in the cerebral cortex. Conclusions: These findings demonstrate that it might be possible to improve cognition of AD patients with a CNTF peptide that has a neurogenic-and neurotrophic-enhancing property.

Molecular Neurodegeneration, 2011

Astrocytes are fundamental for brain homeostasis and the progression and outcome of many neuropat... more Astrocytes are fundamental for brain homeostasis and the progression and outcome of many neuropathologies including Alzheimer's disease (AD). In the triple transgenic mouse model of AD (3xTg-AD) generalised hippocampal astroglia atrophy precedes a restricted and specific β-amyloid (Aβ) plaque-related astrogliosis. Astrocytes are critical for CNS glutamatergic transmission being the principal elements of glutamate homeostasis through maintaining its synthesis, uptake and turnover via glutamate-glutamine shuttle. Glutamine synthetase (GS), which is specifically expressed in astrocytes, forms glutamine by an ATP-dependent amination of glutamate. Here, we report changes in GS astrocytic expression in two major cognitive areas of the hippocampus (the dentate gyrus, DG and the CA1) in 3xTg-AD animals aged between 9 and 18 months. We found a significant reduction in N v (number of cell/mm 3 ) of GS immunoreactive (GS-IR) astrocytes starting from 12 months (28.59%) of age in the DG, and sustained at 18 months (31.65%). CA1 decrease of GS-positive astrocytes N v (33.26%) occurs at 18 months. This N v reduction of GS-IR astrocytes is paralleled by a decrease in overall GS expression (determined by its optical density) that becomes significant at 18 months (21.61% and 19.68% in DG and CA1, respectively). GS-IR N v changes are directly associated with the presence of Aβ deposits showing a decrease of 47.92% as opposed to 23.47% in areas free of Aβ. These changes in GS containing astrocytes and GS-immunoreactivity indicate AD-related impairments of glutamate homeostatic system, at the advanced and late stages of the disease, which may affect the efficacy of glutamatergic transmission in the diseased brain that may contribute to the cognitive deficiency.

Alzheimer's & Dementia, 2010

Current Alzheimer Research, 2011

Alzheimer's disease (AD) affects memory and neurogenesis. Adult neurogenesis plays an important r... more Alzheimer's disease (AD) affects memory and neurogenesis. Adult neurogenesis plays an important role in memory function and impaired neurogenesis contributes to cognitive deficits associated with AD. Increased physical/cognitive activity is associated with both reduced risk of dementia and increased neurogenesis. Previous attempts to restore hippocampal neurogenesis in transgenic mice by voluntary running (RUN) and environmental enrichment (ENR) provided controversial results due to lack of non-transgenic (non-Tg) control and inclusion of social isolation as "standard" housing environment. Here, we determine the effect of RUN and ENR upon hippocampal neurogenesis in a triple transgenic (3xTg-AD) mouse model of AD, which mimics AD pathology in humans. We used single and double immunohistochemistry to determine the area density of hippocampal proliferating cells, measured by the presence of phosphorylated Histone H3 (HH3), and their potential neuronal and glial phenotype by co-localizing the proliferating cells with the immature neuronal marker doublecortin (DCX), mature neuronal marker (NeuN) and specific astroglial marker (GFAP). Our results show that 3xTg-AD mice in control environment exhibit impaired hippocampal neurogenesis compared to non-Tg animals at 9 months of age. Exposure to RUN and ENR housing restores hippocampal neurogenesis in 3xTg-AD animals to non-Tg control levels. Differentiation into neurones and glial cells is affected neither by transgenic status nor by housing environment. These results suggest that hippocampus of 3xTg-AD animals maintains the potential for cellular plasticity. Increase in physical activity and/or cognitive experience enhances neurogenesis and provides a potential for stimulation of cognitive function in AD.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2010

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia... more The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs. Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.

STEM CELLS, 2010

Neural induction is the first step in the formation of the vertebrate central nervous system. The... more Neural induction is the first step in the formation of the vertebrate central nervous system. The emerging consensus of the mechanisms underling neural induction is the combined influences from inhibiting bone morphogenetic protein (BMP) signaling and activating fibroblast growth factor (FGF)/Erk signaling, which act extrinsically via either autocrine or paracrine fashions. However, do intrinsic forces (cues) exist and do they play decisive roles in neural induction? These questions remain to be answered. Here, we have identified a novel neural initiator, neuronatin (Nnat), which acts as an intrinsic factor to promote neural fate in mam-mals and Xenopus. ESCs lacking this intrinsic factor fail to undergo neural induction despite the inhibition of the BMP pathway. We show that Nnat initiates neural induction in ESCs through increasing intracellular Ca 21 ([Ca 21 ] i ) by antagonizing Ca 21 -ATPase isoform 2 (sarco/endoplasmic reticulum Ca 21 -ATPase isoform 2) in the endoplasmic reticulum, which in turn increases the phosphorylation of Erk1/ 2 and inhibits the BMP4 pathway and leads to neural induction in conjunction with FGF/Erk pathway. STEM CELLS

Neural induction is the first step in the formation of the vertebrate central nervous system. The... more Neural induction is the first step in the formation of
the vertebrate central nervous system. The emerging
consensus of the mechanisms underling neural
induction is the combined influences from inhibiting
BMP signaling and activating FGF/Erk signaling,
which act extrinsically via either autocrine or
paracrine fashions. However, do intrinsic forces
(cues) exist and do they play decisive roles in neural
induction? These questions remain to be answered.
Here we have identified a novel neural initiator,
neuronatin (Nnat), which acts as an intrinsic factor to
promote neural fate in mammals and Xenopus.
Embryonic stem (ES) cells lacking this intrinsic
factor fail to undergo neural induction despite the
inhibition of the BMP pathway. We show that Nnat
initiates neural induction in ES cells through
increasing intracellular Ca2+ ([Ca2+]i) by antagonising
Ca2+-ATPase isoform 2 (SERCA 2) in the
endoplasmic reticulum, which in turn increases the
phosphorylation of Erk1/2 and inhibits the BMP4
pathway and leads to neural induction in conjunction
with FGF/Erk pathway.

Cell Death and Disease, 2010

The formation of cerebral senile plaques composed of amyloid b peptide (Ab) is a fundamental feat... more The formation of cerebral senile plaques composed of amyloid b peptide (Ab) is a fundamental feature of Alzheimer's disease (AD). Glial cells and more specifically microglia become reactive in the presence of Ab. In a triple transgenic model of AD (3 Â Tg-AD), we found a significant increase in activated microglia at 12 (by 111%) and 18 (by 88%) months of age when compared with non-transgenic (non-Tg) controls. This microglial activation correlated with Ab plaque formation, and the activation in microglia was closely associated with Ab plaques and smaller Ab deposits. We also found a significant increase in the area density of resting microglia in 3 Â Tg-AD animals both at plaque-free stage (at 9 months by 105%) and after the development of A plaques (at 12 months by 54% and at 18 months by 131%). Our results show for the first time that the increase in the density of resting microglia precedes both plaque formation and activation of microglia by extracellular Ab accumulation. We suggest that AD pathology triggers a complex microglial reaction: at the initial stages of the disease the number of resting microglia increases, as if in preparation for the ensuing activation in an attempt to fight the extracellular Ab load that is characteristic of the terminal stages of the disease.

Progress in Neurobiology, 2012

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cogniti... more Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2010

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia... more The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs. Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribut...

European Journal of Neuroscience, 2010

Alzheimer's disease (AD) is a neurodegenerative disease that deteriorates cognitive functions and... more Alzheimer's disease (AD) is a neurodegenerative disease that deteriorates cognitive functions and associated brain regions such as the hippocampus, being the primary cause of dementia. Serotonin (5-HT) is widely present in the hippocampus, being an important neurotransmitter involved in learning and memory. Although recent evidence suggests alterations in 5-HT neurotransmission in AD, it is not clear how hippocampal 5-HT innervation is modified. Here, we studied hippocampal 5-HT innervation by analysing: (i) the expression, density and distribution of 5-HT transporter (SERT)-immunoreactive fibres; (ii) the specific morphological characteristics of serotonergic fibres and their relation to amyloid plaques; and (iii) the total number of 5-HT neurons within the raphe nuclei in triple transgenic mouse model of AD. We used quantitative light microscopy immunohistochemistry comparing transgenic and nontransgenic animals of different ages (3, 6, 9, 12 and 18 months). The transgenic animals showed a significant increase in SERT fibres in the hippocampus in a subfield-, strata-and age-specific manner. The increase in SERT fibres was specific to the CA1 stratum lacunosum-moleculare. An increase in SERT fibres in transgenic animals was observed at 3 months (by 61%) and at 18 months (by 74%). No changes, however, were found in the total number of raphe 5-HT neurons at any age. Our results indicate that triple transgenic mice display changes in the expression of SERT and increased SERT fibres sprouting, which may account for imbalanced serotonergic neurotransmission associated with (or linked to) AD cognitive impairment.

Frontiers in Neuroanatomy, 2015

Alzheimer's & Dementia, 2010

Aging Cell, 2012

Cell Death and Disease, 2011

Alzheimer's & Dementia, 2010

Molecular Neurodegeneration, 2011

Alzheimer's & Dementia, 2010

Current Alzheimer Research, 2011

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2010

STEM CELLS, 2010

Neural induction is the first step in the formation of the vertebrate central nervous system. The... more Neural induction is the first step in the formation of
the vertebrate central nervous system. The emerging
consensus of the mechanisms underling neural
induction is the combined influences from inhibiting
BMP signaling and activating FGF/Erk signaling,
which act extrinsically via either autocrine or
paracrine fashions. However, do intrinsic forces
(cues) exist and do they play decisive roles in neural
induction? These questions remain to be answered.
Here we have identified a novel neural initiator,
neuronatin (Nnat), which acts as an intrinsic factor to
promote neural fate in mammals and Xenopus.
Embryonic stem (ES) cells lacking this intrinsic
factor fail to undergo neural induction despite the
inhibition of the BMP pathway. We show that Nnat
initiates neural induction in ES cells through
increasing intracellular Ca2+ ([Ca2+]i) by antagonising
Ca2+-ATPase isoform 2 (SERCA 2) in the
endoplasmic reticulum, which in turn increases the
phosphorylation of Erk1/2 and inhibits the BMP4
pathway and leads to neural induction in conjunction
with FGF/Erk pathway.

Cell Death and Disease, 2010

Progress in Neurobiology, 2012

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2010

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia... more The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs. Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribut...

European Journal of Neuroscience, 2010