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A S LaMantia

Publications and source records attributed to A S LaMantia.

At least 19 recordsLinked to original sources
PubMed2001

A role for the cytoskeleton-associated protein palladin in neurite outgrowth.

The outgrowth of neurites is a critical step in neuronal maturation, and it is well established that the actin cytoskeleton is involved in this process. Investigators from our laboratory recently described a novel protein named palladin, which has been shown to play an essential role in organizing the actin cytoskeleton in cultured fibroblasts. We investigated the expression of palladin in the developing rat brain by Western blot and found that the E18 brain contained a unique variant of palladin that is significantly smaller (approximately 85 kDa) than the common form found in other developing tissues (90-92 kDa). Because the expression of a tissue-specific isoform suggests the possibility of a cell type-specific function, we investigated the localization and function of palladin in cultured cortical neurons. Palladin was found preferentially targeted to the developing axon but not the dendrites and was strongly localized to the axonal growth cone. When palladin expression was attenuated by transfection with antisense constructs in both the B35 neuroblastoma cell line and in primary cortical neurons, a reduction in the expression of palladin resulted in a failure of neurite outgrowth. These results implicate palladin as a critical component of the developing nervous system, with an important role in axonal extension.

Actins↗
PubMed2001

Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia.

To account for the complex genetics, the developmental biology, and the late adolescent/early adulthood onset of schizophrenia, the "two-hit" hypothesis has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These early disruptions produce long-term vulnerability to a "second hit" that then leads to the onset of schizophrenia symptoms. The cell-cell signaling pathways involved in nonaxial induction, morphogenesis, and differentiation in the brain, as well as in the limbs and face, could be targets for a "first hit" during early development. These same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be targets for a "second hit" in the adolescent or adult brain. Furthermore, dysregulation of cell-cell signaling by a "first hit" may prime the CNS for a pathologic response to a "second hit" via the same signaling pathway. Thus, parallel disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis in schizophrenia.

Brain↗
PubMed2000

Localization and phosphorylation of Abl-interactor proteins, Abi-1 and Abi-2, in the developing nervous system.

Abl-interactor (Abi) proteins are targets of Abl-family nonreceptor tyrosine kinases and are required for Rac-dependent cytoskeletal reorganization in response to growth factor stimulation. We asked if the expression, phosphorylation, and cellular localization of Abi-1 and Abi-2 supports a role for these proteins in Abl signaling in the developing and adult mouse nervous system. In mid- to late-gestation embryos, abi-2 message is elevated in the central and peripheral nervous systems (CNS and PNS). Abi-1 mRNA is present, but not enhanced, in the CNS, and is not observed in PNS structures. Abi proteins from brain lysates undergo changes in apparent molecular weight and phosphorylation with increasing age. In the postnatal brain, abi-1 and abi-2 are expressed most prominently in cortical layers populated by projection neurons. In cultured neurons, Abi-1 and Abi-2 are concentrated in puncta throughout the cell body and processes. Both Abi and Abl proteins are present in synaptosomes and growth cone particles. Therefore, the Abi adaptors exhibit proper expression patterns and subcellular localization to participate in Abl kinase signaling in the nervous system.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Mesenchymal/epithelial induction mediates olfactory pathway formation.

In the olfactory pathway, as in the limbs, branchial arches, and heart, mesenchymal/epithelial induction, mediated by retinoic acid (RA), FGF8, sonic hedgehog (shh), and the BMPs, defines patterning, morphogenesis, and differentiation. Neuronal differentiation in the olfactory epithelium and directed growth of axons in the nascent olfactory nerve depend critically upon this inductive interaction. When RA, FGF8, shh, or BMP signaling is disrupted, distinct aspects of olfactory pathway patterning and differentiation are compromised. Thus, a cellular and molecular mechanism that facilitates musculoskeletal and vascular development elsewhere in the embryo has been adapted to guide the differentiation of the olfactory pathway in the developing forebrain.

Animals↗
PubMed1999

Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice.

Schizophrenia is thought to be a disease of early development that ultimately affects forebrain neurons and circuits. There may be a relationship between disrupted forebrain development; malformations of the limb, face, and heart; and signaling via the steroid-like hormone retinoic acid (RA) in some schizophrenic patients. The limbs, face, heart, and forebrain all develop from sites where neural crest-derived, RA-producing mesenchyme contributes to induction and differentiation of adjacent epithelia. Induction between neural crest-derived, RA-producing mesenchyme, the anterior neural tube, and the anterior surface epithelium of the embryo guides regional differentiation and pathway formation during forebrain development. Furthermore, there are at least two mouse mutations--in the Pax-6 and Gli-3 genes--that cause peripheral malformations and specifically disrupt neural crest mediated, RA-dependent induction and differentiation in the forebrain. These observations suggest that induction might provide a common target for genes that alter morphogenesis of peripheral structures, disrupt RA-signaling, and compromise forebrain development. In the forebrain, some of these disruptions might influence the numbers or cellular properties of neurons and circuits. Such changes might be reflected in the aberrant forebrain function that characterizes schizophrenia.

Animals↗
PubMed1999

Age-dependent retinoic acid regulation of gene expression distinguishes the cervical, thoracic, lumbar, and sacral spinal cord regions during development.

We evaluated whether differences in the availability of retinoic acid (RA) establish distinct patterns of RA-dependent gene expression in the embryonic mouse thoracic/sacral versus cervical/lumbar spinal cord regions. Exogenous RA elicits ectopic expression of an RA-activated transgene and the RA receptor beta in the dorsal thoracic and sacral cord in mice at embryonic day (E) 12.5, but not E14.5. This age-dependent regulation is cell autonomous and is not accompanied by changes in expression patterns of several retinoid receptors, binding proteins, or the SMRT nuclear corepressor. Instead, this change apparently reflects the loss of endogenous RA in the dorsal thoracic and sacral cord between E12.5 and E14.5. Thus, chronic exposure to exogenous RA between E11.5 and E13.5 restores ectopic RA-mediated gene expression. These observations suggest that the local availability of RA establishes absolute differences in gene expression that distinguish the thoracic and sacral cord from the cervical and lumbar cord during midgestation.

Animals↗
PubMed1998

Retinoid signaling distinguishes a subpopulation of olfactory receptor neurons in the developing and adult mouse.

We asked whether retinoic acid (RA) influences olfactory receptor neurons (ORNs) in the developing and mature mouse olfactory epithelium (oe). The distribution of retinoid receptors and binding proteins in the oe changes between embryonic days 11.5 and 13.5, the period when ORNs first differentiate and send axons into the nascent olfactory nerve. Coincident with this change, RA, which is produced in the frontonasal mesenchyme at these ages, begins to activate gene expression in a bilaterally symmetric subset of ORNs in the dorsolateral oe, as judged by the expression of an RA-responsive transgene. Axons from these RA-activated ORNs are segregated in the olfactory nerve as it extends through the frontonasal mesenchyme toward the forebrain. In vitro, RA potentiates ORN neurite growth on laminin, which, in the embryo, is found in a stripe of frontonasal mesenchyme directly associated with the olfactory nerve. RA does not modify growth on fibronectin, type IV collagen, or L1, which olfactory axons encounter in different regions of the territory between the olfactory epithelium and the brain. The pattern of RA-mediated transcriptional activation and axon segregation persists in early postnatal mice, and RA signaling can be recognized in a subset of adult ORNs in the dorsolateral oe. Thus, RA-mediated gene expression distinguishes a subpopulation of ORNs in a distinct region of the oe during the early development of the olfactory pathway, and may influence differentiation and axonal projections of ORNs in this region throughout life.

Animals↗
PubMed1998

p59fyn and pp60c-src modulate axonal guidance in the developing mouse olfactory pathway.

The Src-family tyrosine kinases p59fyn and pp60c-src are localized on axons of the mouse olfactory nerve during the initial stages of axonal growth, but their functional roles remain to be defined. To study the role of these kinases, we analyzed the trajectory of the olfactory nerve in E11.5 homozygous null mutant mice lacking single src or fyn gens and double mutants lacking both genes. Primary olfactory axons of single and double mutants exited the olfactory epithelium and projected toward the telencephalon, but displayed differences in fasciculation. The fyn-minus olfactory nerve had significantly more fascicles than than src-minus nerve. Most strikingly, the primary olfactory nerve of src/fyn double mutants showed the greatest degree of defasciculation. These defects, identified by NCAM labeling, were not due to apparent changes in the size of the olfactory epithelium. With the exception of the src-minus mice, which had fever fascicles than the wild type, no obvious differences were observed in coalescence of vomeronasal axons from mutant mice. The mesenchyme of the double and single mutants exhibited only subtle changes in laminin and fibronectin staining, indicating that the adhesive environment of the mesenchyme may contribute in part to defects in fasciculation. The results suggest that signaling pathways mediated by p59fyn and pp60c-src contribute to the appropriate fasciculation of axons in the nascent olfactory system, and comprise partially compensatory mechanisms for axonal adhesion and guidance.

Animals↗
PubMed1997

Disruption of local retinoid-mediated gene expression accompanies abnormal development in the mammalian olfactory pathway.

We have evaluated the role of retinoid signaling in the early development of the olfactory epithelium and olfactory bulb. When retinoid-mediated gene expression is blocked briefly in mouse embryos at midgestation with citral (a general alcohol dehydrogenase antagonist that is thought to interfere with retinoid synthesis), the spectrum of morphogenetic abnormalities includes disruption of olfactory pathway development. It is difficult, however, to assess the specificity of this pharmacological manipulation, insofar as it also compromises several other aspects of central nervous system development. In homozygous Pax6 mutant mice (small eye: Pax6(Sey-Neu)), there is a more discrete lesion to the olfactory pathway: The epithelium and bulb cannot be recognized at any time during development, whereas other forebrain subdivisions can still be recognized. This loss of the entire primary olfactory pathway is accompanied by a failure of retinoid-mediated gene expression limited to the frontonasal region and forebrain. Retinoid receptors are expressed in the forebrain of Pax6(Sey-Neu)/Pax6(Sey-Neu) embryos, and the mutant forebrain remains responsive to exogenous retinoic acid. However, in Pax6(Sey-Neu)/ Pax6(Sey-Neu) embryos, retinoic acid (RA) is not produced by the frontonasal mesenchyme, which normally provides local retinoid signals to the placode and forebrain. Together, these results suggest that local retinoid signaling is essential for the normal development of the mammalian olfactory pathway.

Acyclic Monoterpenes↗
PubMed1996

Differential adhesion and the initial assembly of the mammalian olfactory nerve.

During the initial assembly of the olfactory pathway, the behavior of olfactory axons changes as they grow from the olfactory epithelium toward the telencephalic vesicle. The axons exit the epithelium singly or in small fascicles, and their growth cones are simple and bullet-shaped. Outside the epithelium, they make a sharp dorsal turn and fasciculate into a single nerve; the growth cones remain simple. Upon entering the ventromedial telencephalon, the axons defasciculate, branch extensively, and end in complex, lamellate growth cones which extend toward the ventrolateral aspect of the telencephalic vesicle. The distribution of laminin, collagen-IV, and fibronectin varies in register with these changes in olfactory axon and growth cone behavior. Each of these extracellular matrix molecules influences olfactory neurite outgrowth and growth cone morphology in vitro consistent with its distribution in vivo. The distribution of E-cadherin, L1, neural cell adhesion molecule (NCAM) and the polysialated form of NCAM also varies in register with changes in olfactory axon behavior. In vitro, L1 modulates embryonic olfactory neurite outgrowth and growth cone morphology consistent with its distribution in vivo. Thus, olfactory axon trajectory, fasciculation, and growth cone morphology change within distinct adhesive environments in the nascent olfactory pathway, and some of the molecules that characterize these environments have differential effects upon olfactory neurite growth and growth cone morphology. Consequently, the patterned expression and activity of extracellular matrix and cell surface adhesion molecules may contribute to the initial assembly of the olfactory pathway.

Animals↗
PubMed1995

Retinoid signaling and the generation of regional and cellular diversity in the embryonic mouse spinal cord.

Retinoid-dependent gene expression accompanies the emergence of distinct regions and cell classes in the mouse spinal cord around midgestation. We asked whether changes in the expression of retinoid signaling molecules and retinoid-responsive genes reflect the establishment of this regional and cellular diversity. At E10.5, retinoic acid (RA) receptors (RAR)alpha, RAR beta, the retinoid X receptor (RXR) gamma, cellular RA binding protein (CRABP)I, CRAPBII, and cellular retinol binding protein (CRBP)I mRNAs are found throughout the entire anterior-posterior (AP) axis of the cord, as is RA (Colbert et al. [1993] Proc. Natl. Acad. Sci. U.S.A. 90:6572-6576) and RA-sensitive transgene expression (Balkan et al. [1992] Proc. Natl. Acad. Sci. U.S.A. 89:3347-3351). At E12.5, RA, transgene expression, and RAR beta become restricted to the cervical and lumbar cord. RAR alpha, CRABPI, and RXR gamma, however, are found throughout the AP extent. CRABPII and CRBPI, although expanded within the cervical and lumbar regions, are also found throughout the AP axis. Thus, several retinoid signaling molecules continue to be expressed beyond distinct regions of the spinal cord where RA is available and some RA-responsive genes are either restricted or enhanced. Exogenous RA can activate a more widespread response resulting in ectopic transgene and RAR beta expression in the thoracic and sacral cord. Not all RA-sensitive genes, however, respond; CRABPII and CRBPI expression patterns are unchanged. Finally, not every cell within the normal or exogenously induced domains of RA-dependent gene expression responds to RA, nor does every cell express RA receptors or binding proteins. Thus, regional and cellular differences in the distribution of the known retinoid receptors and binding proteins do not predict absolutely where or whether retinoid sensitive genes will be expressed or where retinoids will be available in the developing spinal cord. Instead, retinoid-mediated gene expression in the cervical and lumbar cord seems to reflect retinoid responses that rely both on the local availability of retinoids, the identity of the responding gene, and an indeterminate array of retinoid signaling molecules.

Animals↗
PubMed1995

Distinct adhesive behaviors of neurons and neural precursor cells during regional differentiation in the mammalian forebrain.

Prior to the emergence of the major functional subdivisions of the mammalian forebrain--the neocortex, hippocampus, olfactory bulb, basal ganglia, and basal forebrain--the lateral aspect of the telencephalic vesicle is distinguished by early neuronal differentiation assessed by MAP2 and GAP43 expression and increased expression of the Ca(2+)-independent/immunoglobulin superfamily cell adhesion molecules (CAMs) NCAM, L1, and TAG-1. In contrast, the ventral and medial aspects of the vesicle show little early neuronal differentiation and intermediate or undetectable levels of CAM expression. We asked whether cells from these three regions acquire distinct adhesive and recognition properties that reflect their position, state of neuronal differentiation, and level of CAM expression. In a dissociation/reaggregation assay, cells from the lateral telencephalic vesicle form the largest reaggregates while ventral reaggregates are of intermediate size and medial reaggregates are the smallest. This differential adhesion has a Ca(2+)-independent component, and cells in reaggregates from each region maintain expression of CAMs and other neuronal markers consistent with their region of origin. Furthermore, cells from the lateral telencephalon can specifically sort out from medial cells. Little adhesivity is observed prior to early neuronal differentiation and the expression of Ca(2+)-independent CAMs, when the forebrain is still a prosencephalic vesicle, nor does it follow the pattern of detectable CAM expression once forebrain rudiments are formed. Thus, cells in the early developing forebrain acquire distinct adhesive and recognition properties that reflect the concurrent emergence of regional differences in neuronal differentiation and CAM expression. These differences are transient and can only be detected in the telencephalic vesicle before and during the morphogenesis of rudiments of major forebrain subdivisions.

Animals↗
PubMed1994

Axon overproduction and elimination in the anterior commissure of the developing rhesus monkey.

We have analyzed axon overproduction and elimination in the anterior commissure (AC) of 16 fetal, neonatal, and juvenile rhesus monkeys. Axons are added to the AC at an average rate of 115,000/day during the last two-thirds of gestation, and growth cones are present in a constant proportion to AC axons throughout this period. The peak number of approximately 11 million axons in the AC is reached at birth. Thereafter, axons are eliminated at a net rate of approximately 1 axon/sec during the first 3 postnatal months until the adult number of approximately 3.3 +/- 0.5 million axons is reached. Although there is considerable variability in AC axon number during the period of axon loss, the adult number of AC axons is relatively invariant among the eight adult rhesus monkeys examined. Increase in axon diameter and myelination begins before the major phase of axon elimination and is completed long after the adult number of axons is reached. Apparently, myelinated axons are not eliminated from the AC. Quantitative differences in the magnitude and timing of axon overproduction and elimination in the AC versus that in the corpus callosum (LaMantia and Rakic [1990] J. Neurosci. 10:2156) indicate specific modulation of the development of each commissure, perhaps reflecting differences in the developmental history and functional identity of the distinct cortical regions that give rise to them. This process of overproduction and elimination of AC axons during postnatal development in primates might contribute to individual variations in AC size correlated with a wide range of physical and behavioral differences.

Animals↗
PubMed1993

Local sources of retinoic acid coincide with retinoid-mediated transgene activity during embryonic development.

We have assessed whether retinoic acid (RA) comes from local sources or is available widely to activate gene expression in embryos. We used an RA-responsive indicator cell line, L-C2A5, to localize RA sources. In these cells, an RA-sensitive promoter/lacZ reporter construct used previously by us to produce indicator transgenic mice is induced globally by RA in medium or locally by RA released at physiological concentrations (1 nM) from AG-1X2 resin beads. Furthermore, the cells are differentially responsive to the 9-cis and all-trans isomers of RA at low concentrations. Indicator transgenic mice with the same promoter/reporter construct were used to identify regions of RA-mediated gene activation. There are distinct domains of lacZ expression in the cervical and lumbar spinal cords of embryonic indicator mice. This pattern might reflect localized RA sources or restricted spatial and temporal expression of RA receptors, binding proteins, or other factors. To resolve this issue we compared the pattern of transgene activation in indicator cell monolayers cocultured with normal embryonic spinal cords with that in transgenic spinal cords. The explants induced reporter gene expression in L-C2A5 monolayers in a pattern identical to that in transgenic mice: alar regions of the cervical and lumbar cord were positive whereas those in the thoracic and sacral regions were not. We conclude that restricted sources of RA in the developing spinal cord mediate the local activation of RA-inducible genes. Thus, region-specific gene activation in embryos can be mediated by precisely localized sources of inductive molecules like RA.

Animals↗
PubMed1993

Retinoic acid induction and regional differentiation prefigure olfactory pathway formation in the mammalian forebrain.

We have used an in vitro assay to identify sources of retinoic acid (RA) and transgenic mice to identify target domains in the developing forebrain. RA participates in a sequence of events that leads to the establishment of the olfactory pathway. First, the lateral cranial mesoderm activates an RA-inducible transgene in neuroepithelial cells in the olfactory placode and the ventrolateral forebrain. Then, neurons and neurites begin to differentiate in these two regions. Finally, olfactory axons grow specifically into the ventrolateral forebrain and subsequently are limited to the olfactory bulb rudiment. The coordination of these events, perhaps by common signals, implies that retinoid induction and retinoid-activated region-specific transcriptional regulation may help to define a forebrain subdivision and the peripheral neurons that provide its primary innervation.

Animals↗
PubMed1992

Immunocytochemical localization of DARPP-32, a dopamine and cyclic-AMP-regulated phosphoprotein, in the primate brain.

The localization of DARPP-32, a dopamine and cAMP-regulated phosphoprotein, has been studied in monkey brain by immunocytochemistry. This study indicates that DARPP-32 is enriched in neurons in regions receiving a dense dopamine input from the substantia nigra and ventral tegmental area. Thus, the majority of somata in the anterior olfactory area, nucleus accumbens, caudate nucleus, and putamen are immunoreactive for DARPP-32. In the caudate nucleus, immunoreactive spines receive asymmetric contacts from unlabeled axon terminals. Immunoreactive somata have diameters of 10-15 microns. In regions known to receive projections from these nuclei, immunoreactivity is confined to small puncta that represent axons and axon terminals. Regions in which immunoreactivity is present in puncta include the ventral pallidum, globus pallidus, and substantia nigra pars reticulata. Dopaminergic neurons themselves are not immunoreactive. Neurons containing moderate to weak immunoreactivity for DARPP-32 are observed in portions of the cerebral cortex, particularly in the temporal cortex (layer VI). DARPP-32-positive neurons are also present in the cerebellum, in the medial habenula, and in portions of the bed nucleus of the stria terminalis and amygdaloid complex. DARPP-32 immunoreactivity is also present in astrocytes in the subcortical white matter and in tanycytes in the arcuate nucleus and median eminence. DARPP-32 may be an effective marker for dopaminoceptive neurons in which the actions of dopamine on the D-1 dopamine receptor are mediated through cAMP and its associated protein kinase.

Animals↗