Biomedical subjects

Peter McCaffery

Publications and source records attributed to Peter McCaffery.

15 recordsLinked to original sources

PubMed2006

Retinoic acid signaling and function in the adult hippocampus.

Retinoic acid (RA) is an essential growth factor, derived from vitamin A, which controls growth by activating specific receptors that are members of the nuclear receptor family of transcriptional regulators. Its function in control of growth and differentiation in the embryonic CNS has been extensively investigated, but a role for RA in the mature brain has only recently become apparent. Although the adult CNS has much less capacity for change compared to the embryonic CNS, a limited amount of flexibility, referred to as neural plasticity, still exists. It is these processes that RA influences in the adult brain, including long-term potentiation and neurogenesis. The hippocampus is a brain region dependent upon neural plasticity for its function in learning and memory, and this review focuses on the roles that RA may play in regulating these processes in the adult.

Adult↗

PubMed2005

Macrocephaly and the control of brain growth in autistic disorders.

Autism is a childhood-onset neuropsychiatric disorder characterized by marked impairments in social interactions and communication, with restricted stereotypic and repetitive patterns of behavior, interests, and activities. Genetic epidemiology studies indicate that a strong genetic component exists to this disease, but these same studies also implicate significant environmental influence. The disorder also displays symptomatologic heterogeneity, with broad individual differences and severity on a graded continuum. In the search for phenotypes to resolve heterogeneity and better grasp autism's underlying biology, investigators have noted a statistical overrepresentation of macrocephaly, an indicator of enlarged brain volume. This feature is one of the most widely replicated biological findings in autism. What then does brain enlargement signify? One hypothesis invoked for the origin of macrocephaly is a reduction in neuronal pruning and consolidation of synapses during development resulting in an overabundance of neurites. An increase in generation of cells is an additional mechanism for macrocephaly, though it is less frequently discussed in the literature. Here, we review neurodevelopmental mechanisms regulating brain growth and highlight one underconsidered potential causal mechanism for autism and macrocephaly--an increase in neurogenesis and/or gliogenesis. We review factors known to control these processes with an emphasis on nuclear receptor activation as one signaling control that may be abnormal and contribute to increased brain volume in autistic disorders.

Adaptation, Physiological↗

PubMed2005

Identification, expression analysis, genomic organization and cellular location of a novel protein with a RhoGEF domain.

In this study we describe the identification and characterization of a novel cytosolic protein of the guanine exchange factor (GEF) family. The human cDNA corresponds to predicted human protein FLJ00128/FLJ10357 located on chromosome 14q11.2. The deduced protein sequence contains in its C-terminus a RhoGEF domain followed by a pleckstrin domain. Its N-terminus, central region and RhoGEF/pleckstrin domain are homologous to the recently identified zebrafish Quattro protein, which is involved in morphogenetic movements mediated by the actin cytoskeleton. Based on the homology of our protein's RhoGEF domain to the RhoGEF domains of Trio, Duo and Duet and its homology with Quattro, we named it Solo. The Solo mRNA is ubiquitously expressed but enriched in brain, its expression peaks perinatally and it undergoes extensive alternative splicing. In both myoblasts and neuroblastoma cells, the Solo protein is concentrated around the nucleus.

Amino Acid Sequence↗

PubMed2005

Retinoic acid influences the development of the inferior olivary nucleus in the rodent.

All-trans retinoic acid (atRA) is an endogenous morphogen that regulates gene transcription. Maternal exposure to atRA results in severe developmental abnormalities by disrupting normal patterns of atRA distribution. Previously, we have shown that the pontine nucleus, which originates from the rhombic lip, is severely atrophied in the mouse on exposure to atRA at gestational days 9 and 10. In this study, we show that this same period of atRA exposure has the contrary effect on the inferior olive and this rhombic lip derivative is expanded in volume and probably contains an increased number of cells. The posterior region of the inferior olive maintains a relatively normal shape but is significantly expanded in size. In contrast, the organization of the anterior inferior olive is severely disrupted. Because endogenous atRA levels are known to be higher in the region of the posterior inferior olive at the time of birth of inferior olivary neurons, these results suggest that endogenous atRA may promote the generation, or select the fate, of posterior neurons of the inferior olive. In support of this concept, a reduction in atRA resulting from vitamin A deficiency results in loss of cells of the posterior inferior olive.

Animals↗

PubMed2005

Retinoic acid synthesis by a population of NG2-positive cells in the injured spinal cord.

Retinoic acid (RA) promotes growth and differentiation in many developing tissues but less is known about its influence on CNS regeneration. We investigated the possible involvement of RA in rat spinal cord injury (SCI) using the New York University (NYU) impactor to induce mild or moderate spinal cord contusion injury. Changes in RA at the lesion site were determined by measuring the activity of the enzymes for its synthesis, the retinaldehyde dehydrogenases (RALDHs). A marked increase in enzyme activity occurred by day 4 and peaked at days 8-14 following the injuries. RALDH2 was the only detectable RALDH present in the control or injured spinal cord. The cellular localization of RALDH2 was identified by immunostaining. In the noninjured spinal cord, RALDH2 was detected in oligodendroglia positive for the markers RIP and CNPase. Expression was also intense in the arachnoid membrane surrounding the spinal cord. After SCI the increase in RALDH2 was independent of the RIP- and CNPase-positive cells, which were severely depleted. Instead, RALDH2 was present in a cell type not previously identified as capable of synthesizing RA, that expressed NG2 and that was negative for markers of astrocytes, oligodendroglia, microglia, neurons, Schwann cells and immature lymphocytes. We postulate that the RALDH2- and NG2-positive cells migrate into the injured sites from the adjacent arachnoid membrane, where the RALDH2-positive cells proliferate substantially following SCI. These findings indicate that close correlations exist between RA synthesis and SCI and that RA may play a role in the secondary events that follow acute SCI.

Aldehyde Oxidoreductases↗

PubMed2005

Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons.

Retinoic acid (RA) activity plays sequential roles during the development of the ventral spinal cord. Here, we have investigated the functions of local RA synthesis in the process of motoneuron specification and early differentiation using a conditional knockout strategy that ablates the function of the retinaldehyde dehydrogenase 2 (Raldh2) synthesizing enzyme essentially in brachial motoneurons, and later in mesenchymal cells at the base of the forelimb. Mutant (Raldh2L-/-) embryos display an early embryonic loss of a subset of Lim1+ brachial motoneurons, a mispositioning of Islet1+ neurons and inappropriate axonal projections of one of the nerves innervating extensor limb muscles, which lead to an adult forepaw neuromuscular defect. The molecular basis of the Raldh2L-/- phenotype relies in part on the deregulation of Hoxc8, which in turn regulates the RA receptor RARbeta. We further show that Hoxc8 mutant mice, which exhibit a similar congenital forepaw defect, display at embryonic stages molecular defects that phenocopy the Raldh2L-/- motoneuron abnormalities. Thus, interdependent RA signaling and Hox gene functions are required for the specification of brachial motoneurons in the mouse.

Aldehyde Oxidoreductases↗

PubMed2004

CYP26A1 and CYP26C1 cooperate in degrading retinoic acid within the equatorial retina during later eye development.

In the embryonic mouse retina, retinoic acid (RA) is unevenly distributed along the dorsoventral axis: RA-rich zones in dorsal and ventral retina are separated by a horizontal RA-poor stripe that contains the RA-inactivating enzyme CYP26A1. To explore the developmental role of this arrangement, we studied formation of the retina and its projections in Cyp26a1 null-mutant mice. Expression of several dorsoventral markers was not affected, indicating that CYP26A1 is not required for establishing the dorsoventral retina axis. Analysis of the mutation on a RA-reporter mouse background confirmed, as expected, that the RA-poor stripe was missing in the retina and its projections at the time when the optic axons first grow over the diencephalon. A day later, however, a gap appeared both in retina and retinofugal projections. As explanation, we found that CYP26C1, another RA-degrading enzyme, had emerged centrally in a narrower domain within the RA-poor stripe. While RA applications increased retinal Cyp26a1 expression, they slightly reduced Cyp26c1. These observations indicate that the two enzymes function independently. The safeguard of the RA-poor stripe by two distinct enzymes during later development points to a role in maturation of a significant functional feature like an area of higher visual acuity that develops at its location.

Animals↗

PubMed2004

Ethanol increases retinoic acid production in cerebellar astrocytes and in cerebellum.

Several characteristics of fetal alcohol syndrome (FAS) are similar to the teratogenic effects of retinoic acid (RA) exposure. It has been suggested that FAS may result from ethanol-induced alteration in endogenous RA synthesis, leading to abnormal embryonic concentrations of this morphogen. We examined whether ethanol may interfere with RA synthesis in the postnatal cerebellum, as a region of the developing CNS particularly vulnerable to both ethanol and RA teratogenesis. It was found that astrocytes are the predominant source of postnatal RA synthesis in the cerebellum. They express both retinaldehyde dehydrogenase 1 and 2. In vitro cytosolic preparations of astrocytes, as well as live cell preparations, have an increased capacity to synthesize RA in the presence of ethanol. A mechanism by which ethanol could stimulate RA synthesis is via the ethanol-activated short-chain retinol dehydrogenases, which we show to be present in the postnatal cerebellum. To determine whether ethanol stimulated RA synthesis in vivo, a sensitive and highly specific HPLC/MSn technique was used to measure cerebellar RA after administration of ethanol to postnatal day 4 rat pups. Cerebellar RA levels climbed significantly after such treatment. These results suggest that the cerebellar pathology exerted by ethanol may occur, at least in part, through increased production of RA.

Alcohol Dehydrogenase↗

PubMed2004

13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice.

The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.

Animals↗

PubMed2004

Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration.

Receptor for advanced glycation end products (RAGE) has been proposed as a signal transduction receptor to promote neurite outgrowth and cell migration, by its interaction with a neurite outgrowth promoting protein, Amphoterin. Amphoterin has been shown to interact with sulfoglucuronyl carbohydrate (SGC). The developmental expression of RAGE, Amphoterin and SGC was studied in pre-natal and post-natal mouse cerebellum to establish their cellular and subcellular localization and function. The amount of RAGE in the cerebellum increased with age. RAGE was expressed pre-natally in the external germinal layer and post-natally in the plasma membranes of the granule neurons of the external and internal granule cell layers and in Purkinje cells. Immunocytochemical analysis by high magnification confocal microscopy showed that RAGE was co-expressed with Amphoterin and SGC in the cell surfaces of granule neurons. This co-localization of RAGE, Amphoterin, and SGC was confirmed in isolated and cultured granule neurons and in migrating granule neurons in explant cultures. Anti-RAGE antibodies inhibited neurite outgrowth and cell migration in explant and slice cultures, similar to anti-Amphoterin and anti-SGC antibodies shown previously. The results suggest that RAGE could act as a signaling molecule for neurite outgrowth and cell migration by its interaction with Amphoterin and that of Amphoterin with SGC.

Age Factors↗

PubMed2004

Retinoic acid signaling in the nervous system of adult vertebrates.

The majority of the functions of vitamin A are carried out by its metabolite, retinoic acid (RA), a potent transcriptional activator acting through members of the nuclear receptor family of transcription factors. In the CNS, RA was first recognized to be essential for the control of patterning and differentiation in the developing embryo. It has recently come to light, however, that many of the same functions that RA directs in the embryo are involved in the regulation of plasticity and regeneration in the adult brain. The same intricate metabolic control system of synthetic and catabolic enzymes, combined with cytoplasmic binding proteins, is used in both embryo and adult to create regions of high and low RA to modulate gene transcription. This review summarizes some of the discoveries in the new field of retinoid neurobiology including its functions in neural plasticity and LTP in the hippocampus; its possible role in motor disorders such as Parkinson's disease, motoneuron disease, and Huntington's disease; its role in regeneration after sciatic nerve and spinal cord injury; and its possible involvement in psychiatric diseases such as depression.

Animals↗

PubMed2004

13-cis Retinoic acid (accutane) suppresses hippocampal cell survival in mice.

Use of the acne drug Accutane (13-cis retinoic acid, [13-cis RA]) has been associated with severe depression. This association has been considered controversial because no causative link has been found between 13-cis RA and this disorder. A recent hypothesis has suggested that atrophy of the hippocampus can result in depression. We now show, in a mouse model, that endogenous RA generated by synthetic enzymes in the meninges acts on hippocampal granule neurons, and chronic (3-week) exposure to a clinical dose of 13-cis RA may result in hippocampal cell loss. In humans this may be conjectured to be the mechanism by which Accutane contributes to depression.

Aldehyde Oxidoreductases↗

PubMed2003

The meninges is a source of retinoic acid for the late-developing hindbrain.

One general function for retinoic acid (RA) is pattern organization in the CNS. This regulatory factor has an essential role in spinal cord motor neuron and early posterior hindbrain development. In the anterior CNS, however, there is only a limited number of foci of RA synthesis, and less attention has been placed on regions such as the anterior hindbrain where RA synthesizing enzymes are absent. This study shows that a rich source of RA lies around the hindbrain from the RA synthetic enzyme retinaldehyde dehydrogenase-2 (RALDH2) present in the surrounding meninges and mesenchyme by embryonic day 13. RALDH2 is not distributed uniformly throughout the meninges but is restricted to territories over the developing hindbrain, suggesting that RA signaling may be localized to those regions. Further regulation of RA signaling is provided by the presence of a RA sink in the form of the CYP26B1 RA catabolic enzyme expressed in deeper regions of the brain. As a guide to the neural anatomy of hindbrain RA signaling, we used a mouse transgenic for a lacZ reporter gene driven by a RA response element (RAREhsplacZ) to identify regions of RA signaling. This reporter mouse provides evidence that RA signaling in the hindbrain after embryonic day 13 occurs in the regions of the cerebellum and precerebellar system adjacent to sources of RA, including the inferior olive and the pontine nuclei.

Aldehyde Oxidoreductases↗

PubMed2003

Activation of retinoic acid signalling after sciatic nerve injury: up-regulation of cellular retinoid binding proteins.

In mammalian peripheral nerves a crush lesion causes interactions between injured neurons, Schwann cells and haematogenous macrophages that can lead to successful axonal regeneration. We suggest that the transcriptional activator retinoic acid (RA), takes part in gene regulation after peripheral nerve injury and that RA signalling is activated via the cellular retinoic acid binding protein (CRABP)-II and cellular retinol binding protein (CRBP)-I. With RT-PCR and immunoblotting all necessary components of the RA signalling pathway were detected in the sciatic nerve of adult rats. These are retinoic acid receptors, retinoid X receptors, the retinoic acid synthesizing enzymes RALDH-1, RALDH-2, and RALDH-3, in addition, the cellular retinoid binding proteins CRBP-I, CRABP-I and CRABP-II. Enzyme activity of RALDH-2 was detectable in the nerve, and using a transgenic reporter mouse we found local activation of RA responsive elements in the regenerating nerve. Sciatic nerve crush as well as transection resulted in a more than 10-fold up-regulation of CRBP-I, which is thought to facilitate the synthesis of RA. Both kinds of injury also caused a 15-fold increase in transcript and protein concentration of CRABP-II, a possible mediator of RA transfer to its nuclear receptors.

Aldehyde Oxidoreductases↗

PubMed2002

Retinoid quantification by HPLC/MS(n).

UNLABELLED: Retinoic acid (RA) mediates most of the biological effects of vitamin A that are essential for vertebrate survival. It acts through binding to receptors that belong to the nuclear receptor transcription factor superfamily (Mangelsdorf et al. 1994). It is also a highly potent vertebrate teratogen. To determine the function and effects of endogenous and exogenous RA, it is important to have a highly specific, sensitive, accurate, and precise analytical procedure. Current analyses of RA and other retinoids are labor intensive, of poor sensitivity, have limited specificity, or require compatibility with RA reporter cell lines (Chen et al. 1995. BIOCHEM: Pharmacol. 50: 1257-1264; Creech Kraft et al. 1994. BIOCHEM: J. 301: 111-119; Lanvers et al. 1996. J. Chromatogr. B Biomed. Appl. 685: 233-240; Maden et al. 1998. DEVELOPMENT: 125: 4133-4144; Wagner et al. 1992. DEVELOPMENT: 116: 55-66). This paper describes an HPLC/mass spectrometry/mass spectrometry product ion scan (HPLC/MS(n)) procedure for the analysis of retinoids that employs atmospheric pressure chemical ionization MS. The retinoids are separated by normal-phase column chromatography with a linear hexane-isopropanol-dioxane gradient. Each retinoid is detected by a unique series of MS(n) functions set at optimal collision-induced dissociation energy (30% to 32%) for all MS(n) steps. The scan events are divided into three segments, based on HPLC elution order, to maximize the mass spectrometer duty cycle. The all-trans, 9-cis, and 13-cis RA isomers are separated, if desired, by an isocratic hexane-dioxane-isopropanol mobile phase. This paper describes an HPLC/MS(n) procedure possessing high sensitivity and specificity for retinoids.

Animals↗