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S Hockfield

Publications and source records attributed to S Hockfield.

At least 19 recordsLinked to original sources
PubMed1996

BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines.

Malignant gliomas aggressively invade the surrounding normal brain, whereas brain metastases of nonglial tumors do not. The invasive behavior of gliomas may be mediated by tissue- or tumor-specific extracellular proteins. mRNA for the brain-specific extracellular brain enriched hyaluronan-binding protein (BEHAB) is not detectable in normal adult human cortex or in any nonglioma tumor examined. BEHAB is consistently expressed in surgical samples of glioma (n = 27). Glioma cell lines maintained under standard cell culture conditions or grown as s.c. tumors do not express BEHAB. When grown as intracranial grafts, glioma cell lines that invade the brain express BEHAB, whereas noninvasive cell lines do not. BEHAB is a unique and selective marker for glioma and may play a role in tumor invasion.

Adolescent↗
PubMed1996

The divergent homeobox gene PBX1 is expressed in the postnatal subventricular zone and interneurons of the olfactory bulb.

In the mammalian brain, an important phase of neurogenesis occurs postnatally in the subventricular zone (SVZ). This region consists of a heterogeneous population of cells, some mitotically active, others postmitotic. A subset of mitotically active SVZ precursor cells gives rise to a population of neurons that migrates over a long distance to their final destination, the olfactory bulb. Other SVZ precursor cells continue to proliferate or undergo cell death. The combination of genes that regulates proliferation and cell fate determination of SVZ precursor cells remains to be identified. We have used the rat homolog of the human homeobox gene PBX1 in Northern analysis and in situ hybridization studies to determine the temporal and regional localization of PBX1 expression during embryonic and postnatal rat brain development. PBX1 is expressed embryonically in the telencephalon. In addition, it is expressed at high levels postnatally in the SVZ, in the migratory pathway to the olfactory bulb, and in the layers of the olfactory bulb that are the targets of these migratory neurons. Combining in situ hybridization for PBX1 with immunostaining for markers of cell proliferation (PCNA), postmitotic neurons (class III beta-tubulin), and glia (GFAP), we show that SVZ proliferating cells and their neuronal progeny express rat PBX1 mRNA, whereas glial cells do not express detectable levels of PBX1. The expression of PBX1 in SVZ precursor cells and postmitotic neurons suggests a role for PBX1 in the generation of olfactory bulb interneurons and in mammalian neurogenesis.

Aging↗
PubMed1996

The role of polysialic acid and other carbohydrate polymers in neural structural plasticity.

Polysialic acid (PSA) fulfills several criteria for a molecule involved in structural plasticity, including expression in regions capable of plasticity, re-expression in structures undergoing synaptic rearrangement in the adult, downregulation following innervation, and regulation by activity. In addition, removal of PSA reduces the capacity for structural plasticity. PSA may be paradigmatic for other large polymeric carbohydrates, such as glycosaminoglycans and proteoglycans, which also are highly charged and can be extensively hydrated. These carbohydrates may affect structural plasticity by altering cell-cell and/or cell-matrix interactions by increasing intermolecular spacing through hydration.

Animals↗
PubMed1995

Expression of PTPH1, a rat protein tyrosine phosphatase, is restricted to the derivatives of a specific diencephalic segment.

Studies to date have identified only a few proteins that are expressed in a segment-specific manner within the mammalian brain. Here we report that a nonreceptor protein tyrosine phosphatase, PTPH1, is selectively expressed in the adult thalamus. Expression of PTPH1 mRNA is detected in most, but not all, thalamic nuclei. Nuclei that are derived embryonically from the dorsal thalamus and project to the neocortex express this gene, whereas those derived from the ventral thalamus do not. PTPH1 mRNA expression is also restricted to the dorsal thalamus during development and, thus, can serve as a specific marker for the dorsal thalamic nuclei. Since the subcellular localization of PTPH1 protein is not known, its functional role is not clear. However, the restriction of its expression to the thalamic nuclei that have thalamocortical connections suggests that PTPH1 may play a role in the maintenance of these connections or in determining the physiological properties of thalamic relay nuclei.

Aging↗
PubMed1995

Early postmitotic neurons transiently express TOAD-64, a neural specific protein.

To identify proteins involved in the early development of the mammalian cerebral cortex, we previously used two-dimensional gels to compare proteins synthesized at different stages in corticogenesis in the embryonic rat at embryonic day 14 (E14), E17, and E21. During this period, the cortex develops from a morphologically homogeneous population of proliferative precursor cells into a complex structure containing a diverse array of terminally differentiated neurons. Several proteins are up-regulated coincident with the generation of postmitotic neurons. Here we describe the purification, partial amino acid sequencing, and characterization of one of these proteins, TOAD-64 (Turned On After Division; 64 kDa), using polyclonal antisera to two synthetic peptides from the protein. This analysis reveals that TOAD-64 is a 64,000 Da protein that increases in abundance over the period of corticogenesis and then subsequently decreases to very low levels in the adult. The protein is neural specific and is expressed by postmitotic neurons as they begin their migration out of the ventricular zone into the developing cortical plate. It is expressed in advance of most other neuronal proteins. Progenitor cells do not express TOAD-64. Therefore, this protein is a marker for postmitotic cells that have made a commitment to a neuronal phenotype. The extremely early expression, the relative abundance in newly born neurons, as well as the restriction in expression to the period of initial neuronal differentiation suggest that TOAD-64 may be a key structural protein for early neuronal function.

Amino Acid Sequence↗
PubMed1995

Expression and distribution of phosphorylated MAP1B in growing axons of cultured hippocampal neurons.

Microtubule associated proteins (MAPs) interact with tubulin to modulate neurite stability and growth during development. The phosphorylated form of one of these MAPs, MAP1B (MAP1B-P) is hypothesized to be of particular importance for the regulation of neurite outgrowth. To investigate the mechanisms by which MAP1B and MAP1B-P contribute to this regulation, we used a new antibody against an isoform of MAP1B-P to determine its pattern of expression during neuronal development in vitro. We examined cultured hippocampal neurons because these provide a well-established system to evaluate the development of axons and dendrites. MAP1B, MAP1B-P and MAP2 colocalized to the cell bodies and minor processes during the first 24 hours of culture, but MAP1B-P also extended well into the growth cones. As neurite outgrowth and differentiation proceeded, MAP1B and MAP1B-P became localized to the cell bodies and axons, and MAP2 to the cell bodies and dendrites. After 3 days, MAP1B-P declined in the cell body and was segregated to the distal axon; MAP1B remained in the cell body, but was also concentrated in the distal axon. Over 5-9 days in culture, MAP1B-P levels decreased and became undetectable; MAP1B levels decreased later (19-23 days). MAP2 levels, however, remained high through the entire culture period in cell bodies and dendrites. These results are consistent with the hypothesis that MAP1B-P plays an important role in the initiation and elongation of axons by regulating the dynamics of microtubules near the growth cone: MAP1B-P expression is greatest during the period of active neurite extension, is particularly prominent in growth cones where axon outgrowth is most active, and decreases along with the decline in active axon extension.

Animals↗
PubMed1995

Seven protein tyrosine phosphatases are differentially expressed in the developing rat brain.

Regulation of protein function through tyrosine phosphorylation is critical in the control of many developmental processes, such as cellular proliferation and differentiation. Growing evidence suggests that tyrosine phosphorylation also regulates key events in neural development. Although a large body of data has demonstrated that protein tyrosine kinases play an important role in neural development, much less is known about their counterparts, protein tyrosine phosphatases (PTPases). Using polymerase chain reaction (PCR) with degenerate primers and a neonatal rat cortex cDNA library, we have identified seven PTPases expressed in the developing rat brain. Four of these are transmembrane PTPases: LAR, LRP, RPTP gamma, and CPTP1. Three are nonreceptor PTPases: PTP-1, P19-PTP, and SHP. Northern hybridization analysis demonstrates that only CPTP1 is preferentially expressed in neural tissues, whereas the others are found abundantly in nonneural tissues as well as in the brain. Within the embryonic and early postnatal brain, the seven PTPases have overlapping, yet unique, distributions. For example, LAR mRNA is highly expressed by both proliferating and postmitotic cells in the cerebral cortex at embryonic day 17 and in all layers of the cortex at postnatal day 4. In contrast, RPTP gamma mRNA is expressed by postmitotic neurons in the embryo and predominantly by neurons in the superficial layers of the postnatal cortex. Several of the PTPases examined here are expressed at very high levels in the embryonic cortical plate and postnatal neocortex, including the subplate and subventricular zone. The spatial and temporal regulation of PTPase gene expression suggests that these PTPases have important roles in signal transduction during early neuronal differentiation and neural development.

Animals↗
PubMed1995

Identification of nuclear proteins that are developmentally regulated in embryonic rat brain.

To identify nuclear proteins that might play a role in the acquisition of neuronal phenotype, two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) was used to analyze nuclear proteins expressed over the course of embryonic rat brain development. Metabolically labeled rat brain nuclear proteins from embryonic day 14 (E14) were compared with proteins from embryonic day 20 (E20). Over this period, the rat brain develops from a collection of relatively homogeneous precursor cells into a complex structure containing many different classes of neurons. Computer-assisted analysis of 2D-PAGE fluorograms identified 11 proteins that show increases in their rate of synthesis between E14 and E20. Twenty proteins that consistently appear at E20 are not detectable on fluorograms of E14 nuclear proteins, even after long exposures, and thus may be considered to appear de novo. Fifty-eight proteins show consistent down-regulation between E14 and E20, and of these, 19 are not detectable on fluorograms of E20 nuclear proteins. The electrophoretic properties of many of these proteins suggest that they are previously unreported, developmentally regulated nuclear proteins. Some of the developmentally regulated, brain-enriched nuclear proteins identified here may play a role in regulating the expression of neural genes important for cellular differentiation in the mammalian CNS.

Animals↗
PubMed1995

TOAD-64, a gene expressed early in neuronal differentiation in the rat, is related to unc-33, a C. elegans gene involved in axon outgrowth.

Using two-dimensional gel electrophoresis we previously identified membrane-associated proteins that are upregulated over the course of neurogenesis. One of these, TOAD-64 (Turned On After Division, 64 kDa), is expressed immediately after neuronal birth and is dramatically downregulated in the adult. The gene encoding TOAD-64 has now been cloned, and its sequence shows homology to the unc-33 gene from C. elegans, mutations in which lead to aberrations in axon outgrowth. Northern and in situ hybridization show that TOAD-64 mRNA is enriched in the nervous system and is developmentally regulated in parallel with the protein. The expression of the TOAD-64 protein and gene coincident with initial neuronal differentiation and the downregulation when the majority of axon growth is complete suggests a role in axon elaboration. Three additional lines of evidence support this possibility: TOAD-64 is upregulated following neuronal induction of P19 and PC12 cells; the protein is found in lamellipodia and filopodia of growth cones; and axotomy of the sciatic nerve induces reexpression. While the sequence of TOAD-64 lacks a signal sequence and therefore is likely to encode a cytoplasmic protein, biochemical experiments demonstrate that the protein is tightly, but noncovalently, associated with membranes. The data presented here suggest that TOAD-64 could be a central element in the machinery underlying axonal outgrowth and pathfinding, perhaps playing a role in the signal transduction processes that permit growing axons to choose correct routes and targets.

Aging↗
PubMed1995

The CNS-specific hyaluronan-binding protein BEHAB is expressed in ventricular zones coincident with gliogenesis.

Hyaluronan (HA) is a ubiquitous component of extracellular matrices, and in several systems it plays a central role in regulating cellular proliferation and differentiation. Cell, or tissue,-specific functions of HA are likely to be mediated by cell, or tissue,-specific HA-binding proteins. We previously hyaluronan-binding protein from rat and cat (Jaworski et al., 1994). In view of the potential role of HA in neural differentiation, we examined the expression of BEHAB during late embryonic and early postnatal development of the rat. BEHAB is expressed at very high levels in ventricular zones throughout the neuraxis. Expression is first detected at embryonic day 15 (E15) in the spinal cord, and is detected at progressively more rostral levels at later ages. BEHAB expression, like other features of neural development, follows both caudal-to-rostral and ventral-to-dorsal gradients. The timing of BEHAB expression parallels the timing of the generation of glial cells. In all areas of the CNS examined, BEHAB expression begins after the peak of neurogenesis and coincident with gliogenesis. The regulation of proliferation and differentiation by HA in other tissues, together with the expression of BEHAB in zones of mitotic activity coincident with the generation of glia, suggests that the extracellular matrix protein encoded by BEHAB could play a role in the generation or differentiation of CNS glia.

Aging↗
PubMed1994

Electrical activity in the neuromuscular unit can influence the molecular development of motor neurons.

During the first few weeks of postnatal life spinal motor neurons develop electrophysiological, morphological, and molecular features that are characteristic of adult motor neurons. To understand how the acquisition of the mature neuronal phenotype is regulated, we have examined the expression of the motor neuron cell surface proteoglycan recognized by monoclonal antibody Cat-301 in the hamster. Previously we found that Cat-301 immunoreactivity is not present on motor neurons at birth and that by the end of the second postnatal week all motor neurons are Cat-301-positive. Surgical and pharmacological lesion studies have shown that the onset of Cat-301 expression depends upon input from both large-diameter primary afferents and from supraspinal afferents. Once the Cat-301 proteoglycan is expressed on motor neurons, its continued expression is independent of these inputs. These studies suggested that motor neuron maturation depends upon the coordination of several afferent inputs during the first postnatal weeks of life. Our previous studies could not address whether segmental and descending afferents (i) provide a chemical signal (such as a trophic factor) or (ii) confer a pattern of neuronal activity upon motor neurons that then results in the expression of the Cat-301 proteoglycan. The present experiments examine the role of electrical activity in motor neuron maturation. In normal animals, all sciatic motor neurons are Cat-301-positive by Postnatal Day 19 (P19). Chronic application of the sodium channel blocker, tetrodotoxin (TTX), to the sciatic nerve in neonatal animals reduces the percentage of Cat-301-positive motor neurons found at P21 by one-third. This reduction is not due to a nonspecific inhibition of all protein synthesis, because the expression of two other motor neuron antigens proceeds normally in TTX-treated neonates. Blockade of neuromuscular transmission in neonates by Botulinus toxin A also reduces the percentage of Cat-301-positive motor neurons. Cat-301 expression is not tied simply to neuronal activity, because chronic application of TTX to the sciatic nerve, or Botulinus toxin A to muscles, in the adult does not reduce Cat-301 expression. These findings indicate that electrical activity generated within the neuromuscular unit in early postnatal life can influence the acquisition of mature molecular properties by motor neurons.

Action Potentials↗
PubMed1994

BEHAB, a new member of the proteoglycan tandem repeat family of hyaluronan-binding proteins that is restricted to the brain.

Hyaluronan (HA) is a ubiquitous component of the extracellular matrix of all tissues. In the mammalian central nervous system (CNS) HA is present throughout development and into adulthood. While the functions of HA are likely to be mediated by HA-binding proteins, no cell or tissue specific HA-binding proteins have been reported. In an effort to characterize the composition of the extracellular matrix of the CNS, we sought to identify neural HA-binding proteins. We report here the isolation and characterization of a cDNA with a high degree of sequence homology to members of the proteoglycan tandem repeat (PTR) family of HA-binding proteins. Unlike other HA-binding proteins, the expression of this cDNA is restricted to the CNS. We propose the name BEHAB, Brain Enriched HyAluronan Binding protein, for this gene. The expression of BEHAB mRNA is developmentally regulated; expression is first detected in the late embryonic period and peaks during the first two postnatal weeks. In the embryo, BEHAB is expressed at highest levels in mitotically active cells. The sequence of BEHAB has long stretches of identity between rat and cat, suggesting that the encoded protein is functionally important. The size and sequence of BEHAB are consistent with the possibility that it could serve a function like link protein, stabilizing interactions between HA and brain proteoglycans. These observations suggest that existence of other tissue specific HA-binding proteins.

Amino Acid Sequence↗
PubMed1993

Expression of the mas proto-oncogene in the rat hippocampal formation is regulated by neuronal activity.

The mas proto-oncogene encodes a seven membrane-spanning G-protein-coupled receptor which is activated by angiotensins. In the postnatal and adult rat, mas mRNA is specifically expressed at high levels in hippocampal neurons. We report here using in situ hybridization and RNase protection that brief seizure episodes lead to a significant and transient increase in mas mRNA in the hippocampus. Increased levels of mas transcripts were detected 2, 4, and 6 h following seizure. By 24 h post seizure, baseline levels were detected. The presumed subsequent increase of the mas receptor protein may contribute to anatomical and physiological plasticity that is associated with intense activation of hippocampal pathways.

Animals↗
PubMed1993

Activity-dependent structural changes during neuronal development.

Activity during the early postnatal period can have a pronounced effect on the structure of neurons in the central nervous system. Recent studies in the cat visual system and in the vertebrate and invertebrate neuromuscular system, have provided new insights into the cellular and molecular features of this process.

Animals↗
PubMed1993

Protein tyrosine phosphatases expressed in the developing rat brain.

Previous studies of the developing nervous system have shown that cell-cell and cell-matrix interactions are involved in a variety of processes such as the proliferation, migration, and differentiation of neurons. While many cell-surface molecules have been identified, the signal transduction mechanisms through which they modify cellular responses are poorly understood. Recent studies have described a new and large family of enzymes, protein tyrosine phosphatases (PTPases), that may play a key role in transduction of cell surface events. Opposing the actions of protein tyrosine kinases (PTKs), PTPases can determine the state of tyrosine phosphorylation of a protein and regulate its function. Within the family of PTPases, two subgroups have been characterized: low-molecular-weight cytoplasmic (nonreceptor) PTPases and high-molecular-weight transmembrane (receptor) PTPases. Many receptor PTPases have fibronectin type III and/or Ig-like domains in their extracellular domains, suggesting that they have dual functions: cell adhesion and signal transduction. Such molecules may play a role in cellular recognition events that mediate the accurate assembly of the nervous system. Using polymerase chain reaction with degenerate primers and a neonatal rat cortex cDNA library, we have identified a number of putative PTPase domains expressed in brain. Three are characterized here. These three sequences are most abundantly expressed in the developing cortex and so are named cortex-enriched protein tyrosine phosphatases (CPTPs) 1, 2, and 3. CPTP1 and CPTP3 show sequence homology to receptor PTPases and detect multiple high-molecular-weight mRNAs that are expressed preferentially in the developing CNS. Analysis of a longer cDNA indicates that CPTP1 and CPTP3 are the first and second phosphatase domains of a single receptor PTPase. CPTP2 identifies a single, smaller mRNA species with sequence homology to nonreceptor PTPases. Within the CNS, mRNAs detected by all three CPTPs are expressed at highest levels during prenatal and early postnatal days and are downregulated in the adult. In situ hybridization demonstrates that the CPTPs are expressed by progenitor cells and developing neurons. The spatial and temporal regulation of CPTPs suggests that they may play a role in neuronal development.

Aging↗
PubMed1992

N-methyl-D-aspartate receptors are transiently expressed in the developing spinal cord ventral horn.

Quantitative receptor autoradiography was used to map the distribution of N-methyl-D-aspartate (NMDA) receptors in the developing rat spinal cord. Three different specific ligands, which label partially overlapping subpopulations of NMDA receptors, were used: an agonist (L-[3H]glutamate), a noncompetitive antagonist ([3H]MK-801), and a competitive antagonist ([3H]CGP-39653). In the adult, NMDA receptors labeled with all three ligands are restricted to the substantia gelatinosa in the spinal dorsal horn. In marked distinction, at postnatal day 7 NMDA receptors labeled with L-[3H]glutamate and [3H]MK-801 are present throughout the spinal gray matter. NMDA receptors in the neonatal spinal ventral horn have a higher affinity for L-[3H]glutamate than those in the adult substantia gelatinosa. Over the second and third postnatal weeks, NMDA receptors are lost from all areas of the spinal gray matter except for the substantia gelatinosa. Neonatal NMDA receptors identified with [3H]CGP-39653 are restricted to the substantia gelatinosa. These results show that the immature ventral horn contains a subpopulation of NMDA receptors and raise the possibility that motor neurons transiently express NMDA receptors in early postnatal life. Ventral horn NMDA receptors may be a component of the mechanisms by which the mature phenotype of motor neurons is acquired through activity-dependent processes. The loss of NMDA receptors over the course of development may play a role in limiting the period of motor neuron plasticity.

2-Amino-5-phosphonovalerate↗
PubMed1992

The mas proto-oncogene is developmentally regulated in the rat central nervous system.

The mas proto-oncogene encodes a protein with a predicted structure similar to members of the family of seven transmembrane domain spanning receptors. These receptors are thought to transduce extracellular signals to G-proteins. Angiotensin II and III have been reported to be the functional ligands for the mas oncogene-encoded receptor (Jackson et al., 1988). We show here using in situ hybridization histochemistry and RNase protection assays that mas mRNA is expressed in a subpopulation of neurons in both the adult and developing rat CNS. In the adult CNS, mas mRNA is most abundant in hippocampal pyramidal neurons and dentate granule cells; mas transcripts are also present at low levels in the cortex and thalamus. mas is first expressed in the developing rat CNS at postnatal day 1 (P1). Even at this early stage in CNS development the pattern of mas expression is similar to that seen in the adult. Although at P1 most neurons of the dentate gyrus are not yet generated and cells of the hippocampal CA fields are undergoing migration and synaptogenesis (Bayer 1980; Altman and Bayer, 1990a, 1990b, 1990c), mas is specifically expressed in these cell populations. This extremely restricted pattern of expression suggests that mas may function in determining the morphology and connections of specific cell types in the hippocampus. This function may in part be carried out by the ability of mas to link external cues to intracellular processes.

Animals↗