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A J Hannan

Publications and source records attributed to A J Hannan.

15 recordsLinked to original sources
PubMed2001

PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex.

During development of the cerebral cortex, the invasion of thalamic axons and subsequent differentiation of cortical neurons are tightly coordinated. Here we provide evidence that glutamate neurotransmission triggers a critical signaling mechanism involving the activation of phospholipase C-beta1 (PLC-beta1) by metabotropic glutamate receptors (mGluRs). Homozygous null mutation of either PLC-beta1 or mGluR5 dramatically disrupts the cytoarchitectural differentiation of 'barrels' in the mouse somatosensory cortex, despite segregation in the pattern of thalamic innervation. Furthermore, group 1 mGluR-stimulated phosphoinositide hydrolysis is dramatically reduced in PLC-beta1-/- mice during barrel development. Our data indicate that PLC-beta1 activation via mGluR5 is critical for the coordinated development of the neocortex, and that presynaptic and postsynaptic components of cortical differentiation can be genetically dissociated.

Animals↗
PubMed2000

N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant condition involving progressive neurodegeneration, primarily the corpus striatum and cerebral cortex. We have used in vivo magnetic resonance spectroscopy (MRS) to assess specific neuronal markers in transgenic mice (R6/1 line) expressing exon I of the human huntingtin gene with an expanded CAG repeat. Levels of N-acetylaspartate (NAA), an indicator of healthy neuronal function, were significantly reduced (26%) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age. However, levels of cholines and creatine-phosphocreatine were not altered in the HD mice. Expression of dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and, even more dramatically, at 11 months of age. In contrast, expression of calbindin was not significantly decreased in HD mice. Our results suggest that the observed decreases in DARPP-32 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD.

Animals↗
PubMed2000

CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.

A novel, brain-specific cDNA, denoted CROC-4, was cloned from human brain by a contingent replication of cDNA procedure capable of detecting transcriptional activators of the human c-fos proto-oncogene promoter. CROC-4 encoded an 18-kDa serine/threonine-rich polypeptide containing a P-loop motif and an SH3-binding region with phosphorylation sites for a variety of protein kinases (cdc2, CDK2, MAPK, CDK5, protein kinase C, Ca(2+)/calmodulin protein kinase 2, casein kinase 2) involved in cell proliferation and differentiation. Immunohistochemistry revealed that during early development, expression was associated with proliferating and migrating cells throughout the rodent brain, initially appearing in the proliferative ventricular zones. During late development and in adult human brain, CROC-4 was expressed in diverse brain regions including the thalamus, subthalamic nucleus, corpus callosum, substantia nigra, caudate nucleus, amygdala, and hippocampus. The association of CROC-4 expression with proliferating regions of developing brain and retention in regions of the adult brain, as well as the punctate nuclear location, suggest that CROC-4 participates in brain-specific c-fos signaling pathways involved in cellular remodeling of brain architecture.

Adult↗
PubMed1999

Expression of doublecortin correlates with neuronal migration and pattern formation in diverse regions of the developing chick brain.

The development of functional layers in the brain involves spatially and temporally regulated gene expression. Through cDNA library screening, we have identified genes that are expressed in a neural-specific manner during brain development. Sequencing and expression data indicate that one of the clones, 18C15, is the chick homologue of doublecortin, a human X-linked gene found to be mutated in subcortical laminar heterotopia (double cortex syndrome) and lissencephaly. The 18C15 mRNA contains multiple motifs that are known to regulate mRNA stability in response to inductive signals, and these motifs are conserved between the chick and human sequences. Doublecortin is found to be expressed at peak levels during early development of the cerebellum and forebrain, and is expressed in other regions including the tectum, spinal cord, and dorsal root ganglia. This study demonstrates both spatial and temporal regulation of doublecortin expression in the chick, which is associated with early events in brain development, including neuronal migration.

3' Untranslated Regions↗
PubMed1999

Characterization of nodular neuronal heterotopia in children.

Neuronal heterotopia are seen in various pathologies and are associated with intractable epilepsy. We examined brain tissue from four children with subcortical or periventricular nodular heterotopia of different aetiologies: one with severe epilepsy following focal brain trauma at 17 weeks gestation, one with hemimegalencephaly and intractable epilepsy, one with focal cortical dysplasia and intractable epilepsy, and one dysmorphic term infant with associated hydrocephalus and polymicrogyria. The connectivity of nodules was investigated using histological and carbocyanine dye (DiI) tracing techniques. DiI crystal placement adjacent to heterotopic nodules revealed numerous DiI-labelled fibres within a 2-3 mm radius of the crystals. Although we observed labelled fibres closely surrounding nodules, the majority did not penetrate them. Placement of DiI crystals within nodules also identified a limited number of projections out of the nodules and in one case there was evidence for connectivity between adjacent nodules. The cellular and neurochemical composition of nodules was also examined using immunohistochemistry for calretinin and neuropeptide Y (NPY), which are normally expressed in GABAergic cortical interneurons. Within heterotopic nodules from all cases, numerous calretinin-positive neurons were identified, along with a few cell bodies and many processes positive for NPY. Calretinin-positive neurons within nodules were less morphologically complex than those in the cortex, which may reflect incomplete differentiation into an inhibitory neuronal phenotype. There were also abnormal clusters of calretinin-positive cells in the overlying cortical plate, indicating that the migratory defect which produces heterotopic nodules also affects development of the cortex itself. Thus, heterotopic nodules consisting of multiple neuronal cell types are associated with malformation in the overlying cortical plate, and have limited connectivity with other brain regions. This abnormal development of connectivity may affect neuronal maturation and consequently the balance of excitation and inhibition in neuronal circuits, leading to their epileptogenic potential.

Brain Chemistry↗
PubMed1998

Structural compartments within neurons: developmentally regulated organization of microfilament isoform mRNA and protein.

The microfilament system is thought to be a crucial cytoskeletal component regulating development and mature function of neurons. The intracellular distribution of the microfilament isoform components, actin and tropomyosin (Tm), in neurons primarily in vivo, has been investigated at both the mRNA and the protein level using isoform specific riboprobes and antibodies. Our in vivo and in vitro studies have identified at least six neuronal compartments based on microfilament isoform mRNA localization: the developing soma, the mature soma, growth cone, developing axon hillock/proximal axon, mature somatodendritic and mature axonal pole soma. Protein localization patterns revealed that the isoforms were frequently distributed over a wider area than their respective mRNAs, suggesting that isoform specific patterns of mRNA targeting may influence, but do not absolutely determine, microfilament isoform location. Tm4 and Tm5 showed identical mRNA targeting in the developing neuron but distinct protein localization patterns. We suggest that in this instance mRNA location may best be viewed as a regulated site of synthesis and assembly, rather than a regulator of protein localization per se. In addition, Tm5 and beta-actin mRNA and protein locations were developmentally regulated, suggesting the possibility that environmental signals modulate targeting of specific mRNAs and their proteins. Thus, developmentally regulated mRNA localization and positional translation may act in concert with protein transport to regulate neuronal microfilament composition and consequently neuronal structure.

Actin Cytoskeleton↗
PubMed1996

Differential induction and intracellular localization of SCG10 messenger RNA is associated with neuronal differentiation.

The differentiation of neurons involves the establishment of distinct molecular compartments which regulate neuronal shape and function. This requires targeting of specific gene products to growth-associated regions of the neuron. We have investigated the temporal and spatial regulation of SCG10 gene expression during neuronal differentiation. There are two SCG10 messenger RNAs, 1 and 2 kg in length, which encode the same growth-associated protein. These messenger RNAs were found to be differentially regulated during the onset of neurite outgrowth in early rat cerebellum development. In PC12 cells, the two SCG10 messenger RNAs were shown to be differentially induced by nerve growth factor. Regulation of the 2 kb messenger RNA, but not the 1 kb messenger RNA, is dependent on the differentiation of PC12 cells, indicating that post-transcriptional regulation of SCG10 expression during neurite outgrowth. Spatial regulation of the 2 kb SCG10 messenger RNA distribution during brain development was examined by in situ hybridization. The 2 kb messenger RNA was found to be localized to the neuronal pole where outgrowth was occurring, within differentiating neurons in vivo. Intracellular localization of SCG10 messenger RNA was also observed in differentiating primary cultured neurons, with the 2 kb messenger RNA transported into growing neurites during the development of neuronal polarity. In neurons which had developed polarity, the 2 kb SCG10 messenger RNA was consistently found in the cell body and axon. This study demonstrates both temporal and spatial post-transcriptional regulation of SCG10 expression which is associated with neurite outgrowth. The directed transport and positional translation of SCG10 messenger RNA provide a potential mechanism for protein targeting and the creation of molecular compartments during neuronal differentiation.

Amino Acid Sequence↗
PubMed1996

Trinucleotide-repeat expansions and neurodegenerative disease: a mechanism of pathogenesis.

1. Studies of a number of hereditary neurodegenerative diseases, the most common of which is Huntington's disease, have identified the expansion of trinucleotide repeats as a common causative mutation. 2. The diseases are caused by expansions of CAG repeats, encoding polyglutamine tracts, within the coding regions of a variety of unrelated genes. The mechanism whereby this specific genetic instability leads to selective neurodegeneration is currently unknown. 3. Our current understanding of these polyglutamine expansion neurodegenerative diseases is outlined. A potential mechanism is discussed whereby subtle alterations in glutamine, and consequently glutamate levels, may induce chronic excitotoxicity and slow cell death in neuronal populations possessing specific glutamate receptors. The potential role of glutamate receptor-mediated changes to intracellular calcium levels and energy metabolism in the neurodegenerative pathway is also addressed.

Animals↗
PubMed1995

Intracellular localization of tropomyosin mRNA and protein is associated with development of neuronal polarity.

Neuronal differentiation involves extensive rearrangement of the cytoskeleton, including the actin-based microfilament system, and establishment of molecular compartments within the neuron. The intracellular distribution of tropomyosin (Tm) mRNA in vivo and in vitro has been examined and correlated with protein targetting. The mRNAs encoding two Tm isoforms were found to be differentially localized in developing neurons. Tm-5 mRNA is localized to the axonal pole of differentiating embryonic rat neurons, in contrast to TmBr-2 mRNA distribution throughout the cell body. Tm-5 mRNA is transported into the axon of differentiating primary cultured neurons. This mRNA localization is developmentally regulated and correlates with the targeting of Tm-5 protein to growing axons. Tm-5 colocalizes with a subset of neuronal microfilaments associated with the initiation and maintenance of outgrowth. The segregation of Tm-5 is the earliest known marker of neuronal polarity and may play a role in the establishment of polarity.

Animals↗
PubMedDate not supplied

Phospholipase C-beta1 expression correlates with neuronal differentiation and synaptic plasticity in rat somatosensory cortex.

Receptor-mediated signal transduction is thought to play an important role in neuronal differentiation and the modification of synaptic connections during brain development. The intracellular signalling molecule phospholipase C-beta1 (PLC-beta1), which is activated via specific neurotransmitter receptors, has recently been implicated in activity-dependent plasticity in the cat visual cortex. PLC-beta1 has been shown to be concentrated in an intermediate compartment-like organelle, the botrysome, which is present in 5-week-old, but not adult, cat cortical neurons. We have characterized the spatial and temporal regulation of PLC-beta1 expression in the developing rat cerebral cortex. PLC-beta1-positive botrysome-like organelles are observed during early postnatal cortical development, but not at postnatal day 14 or later stages. In the postnatal somatosensory cortex, there is also striking spatial variation in diffuse neuropilar immunoreactivity of layer IV and above, in a pattern corresponding to the thalamocortical recipient zones known as barrels. This expression pattern is specific to the developing barrel field and is most distinct at postnatal days 4-7, when cellular components of barrels are capable of activity-dependent modification. During later stages of cortical maturation, stained botrysomes disappear, expression of PLC-beta1 is down-regulated and only diffuse immunoreactivity remains in dendritic processes. Our results are consistent with a role for PLC-beta1 in activity-dependent, receptor-mediated neuronal plasticity during development of the somatosensory cortex.

Animals↗
PubMedDate not supplied

Anterior cingulate cortical transplantation in transgenic Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant disorder involving progressive neurodegeneration of the corpus striatum and cerebral cortex. Transgenic mice, in which exon 1 of the human HD gene with an expanded trinucleotide repeat is expressed, develop a neurodegenerative syndrome that closely models human HD. Transplantation of wild-type donor cortex into the anterior cingulate cortex of neonatal HD mice (R6/1 line) was found to delay the onset of a specific motor deficit, rear-paw clasping. However, transplantation did not significantly enhance motor performance on a suspended horizontal rod, a behavioural measure of fine motor co-ordination. Control experiments in which the anterior cingulate cortex was resected, but no donor cortical tissue was transplanted, showed no behavioural benefit. In fact, wild-type littermate mice that also underwent this surgical resection, were found to develop motor deficits similar to those exhibited by non-resected HD mice. These results suggest that the anterior cingulate cortex is an important area of pathology in this HD model, and that therapeutic approaches to HD may need to target cortical, as well as striatal areas.

Animals↗