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Biomedical subjects

W D Snider

Publications and source records attributed to W D Snider.

At least 37 records · Page 2Linked to original sources
PubMed1997

Initial trajectories of sensory axons toward laminar targets in the developing mouse spinal cord.

The formation of laminar-specific projections is a key event in the development of appropriate neuronal connections in many regions of the central nervous system. In order to provide a framework for defining functions of molecules related to spinal laminar targeting of dorsal root ganglion neurons in mice, we have characterized the initial trajectories of sensory axons in relation to the maturation of their target laminae in the spinal cord. We show that morphological and biochemical differentiation of distinct clusters of neurons in the dorsal region of the spinal cord precedes initial collateral branching from sensory axons. Between embryonic day (E) 12.5 and E13.5, sensory axons develop swelling ("nodes") along their entire intraspinal extent and elaborate interstitial collateral branches from these nodes. Collaterals from the different classes of sensory axons then penetrate the gray matter of the spinal cord sequentially. Each class of sensory axons projects directly to its target lamina, never branching into inappropriate laminae en route. Some cutaneous afferents traverse the entire width of the spinal cord to reach superficial laminae on the contralateral side, strictly avoiding both the ventral spinal cord and inappropriate laminae of the deep dorsal horn. The pathways taken by developing sensory afferents are compatible with the idea that cells in inappropriate laminae exert inhibitory influences on sensory axons which regulate their laminar specificity.

Afferent Pathways↗
PubMed1997

Distribution of the ten known laminin chains in the pathways and targets of developing sensory axons.

Laminins are heterotrimers of alpha, beta, and gamma chains. At present, five alpha, three beta, and two gamma chains have been described. The best characterized laminin (laminin 1 = alpha 1, beta 1, gamma 1) promotes neurite outgrowth from virtually all classes of developing neurons, implying that laminins may serve as axon guidance molecules in vivo. Moreover, different laminin trimers exert distinct effects on subsets of laminin-1-responsive cells, suggesting that isoform diversity may underlie some axonal choices in vivo. As a first step toward evaluating these hypotheses, we have documented the expression patterns of all 10-known laminin chains in the peripheral nervous system and spinal cord of the murine embryo. The alpha 2, alpha 4, beta 1, and gamma 1 chains are expressed in peripheral axonal pathways by embryonic day (E) 11.5, when sensory and motor axonal outgrowth is underway. Thus, laminins (but not laminin 1) may promote peripheral axonal outgrowth. By E 13.5, laminin chains are differentially expressed in the limb-bud, with prominent expression of alpha 2 and alpha 4 in muscle and of alpha 3 and alpha 5 in skin. This pattern raises the possibility that laminin isoform diversity contributes to the ability of cutaneous and muscle sensory axons to distinguish their targets. Later in development, some chains (e.g., alpha 2, alpha 4, and beta 1) are downregulated in peripheral nerve while others (e.g., gamma 1), continue to be expressed by Schwann cells into adulthood. In contrast to peripheral nerves and ganglia, laminin chains are expressed at low levels, if at all, in the developing spinal cord gray matter.

Amino Acid Sequence↗
PubMed1997

Cloning and expression of a novel murine semaphorin with structural similarity to insect semaphorin I.

We describe a novel semaphorin family member, Sema VIa, with 25-36% sequence identity at the amino acid level in the semaphorin domain to previously published mouse homologues. This novel family member shares considerable homology with the best characterized murine semaphorin, Sema III (also known as SemD), at the 5' end but is divergent from Sema III near the 3' end because it contains a putative transmembrane domain. Remarkably, of the known semaphorins, Sema VIa bears the greatest structural similarity to insect Sema I, although it contains a much larger intracellular domain. We propose, therefore, that Sema VIa is the prototype of a new class (class VI) of semaphorins. In order to gain insights into potential functions of Sema VIa, we have compared mRNA expression of Sema VIa to that of Sema III during development. In the nervous system, Sema VIa is expressed in strikingly localized and transient patterns that are markedly different from those of Sema III. Interestingly, Sema VIa and Sema III frequently exhibit complementary or adjacent loci of expression. We suggest that Sema VIa may be important to nervous system development via a mechanism that involves cell-cell communication.

Amino Acid Sequence↗
PubMed1997

Introduction of a neurotrophin-3 transgene into muscle selectively rescues proprioceptive neurons in mice lacking endogenous neurotrophin-3.

To clarify the role of muscle-derived neurotrophin-3 (NT-3) in the development of sensory neurons, we generated transgenic mice selectively overexpressing NT-3 in skeletal muscles under the control of a myogenin promoter (myo-NT-3 mice). The myo-NT-3 transgene was then bred into an NT-3 null mutant (-/-) line to generate myo-NT-3, NT-3(-/-) mice in which NT-3 was expressed in muscles, but not elsewhere. Transient overexpression of NT-3 in developing muscles increased the number of proprioceptive neurons as well as the density of both their central and peripheral projections, resulting in more Ia afferents in spinal cord and more spindles (end organs of Ia afferents) in muscles. NT-3 expression restricted to muscles was sufficient to secure the development of proprioceptive neurons and their central and peripheral projections in myo-NT-3, NT-3(-/-) mice. The loss of nonproprioceptive neurons observed in NT-3(-/-) mice was not reversed by the transgene, suggesting that these neurons are regulated by NT-3 from sources other than muscle. We conclude that target-derived rather than intraganglionic NT-3 is preeminent in supporting the development of proprioceptive neurons. The level of NT-3 in developing muscles may be the principal factor determining the number of proprioceptive neurons in dorsal root ganglions and spindles in skeletal muscles of adults.

Afferent Pathways↗
PubMed1997

IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.

We have tested the role of glial cell line-derived neurotrophic factor (GDNF) in regulating a group of putatively nociceptive dorsal root ganglion (DRG) neurons that do not express calcitonin gene-related peptide (CGRP) and that downregulate the nerve growth factor (NGF) receptor tyrosine kinase, TrkA, after birth. We show that mRNA and protein for the GDNF receptor tyrosine kinase, Ret, are expressed in the DRG in patterns that differ markedly from those of any of the neurotrophin receptors. Most strikingly, a population of small neurons initiates expression of Ret between embryonic day 15.5 and postnatal day 7.5 and maintains Ret expression into adulthood. These Ret-expressing small neurons are selectively labeled by the lectin IB4 and project to lamina IIi of the dorsal horn. Ret-expressing neurons also express the glycosyl-phosphatidyl inositol-linked (GPI-linked) GDNF binding component GDNFR-alpha and retrogradely transport 125I-GDNF, indicating the presence of a biologically active GDNF receptor complex. In vitro, GDNF supports the survival of small neurons that express Ret and bind IB4 while failing to support the survival of neurons expressing TrkA and CGRP. Together, our findings suggest that IB4-binding neurons switch from dependence on NGF in embryonic life to dependence on GDNF in postnatal life and are likely regulated by GDNF in maturity.

Aging↗
PubMed1996

Synchronous onset of NGF and TrkA survival dependence in developing dorsal root ganglia.

Determinations of dorsal root ganglion (DRG) neuron loss in nerve growth factor (NGF) and neurotrophin-3 (NT-3) null mutant mice have supported the concept that neurons can switch neurotrophin dependence by revealing that many neurons must require both of these factors acting either sequentially or simultaneously during development. The situation is complex, however, in that NT-3(-/-) mutant mice show far greater neuron loss than mice deficient in the NT-3 receptor TrkC, suggesting that NT-3 may support many DRG neurons via actions on the NGF receptor TrkA. To assess the possibility of ligand-receptor cross-talk as a developmental mechanism, we have compared the onset of survival dependence of lumbar DRG neurons on NT-3, TrkC, NGF, and TrkA signaling in mice deficient in these molecules as a result of gene targeting. At embryonic day 11.5 (E11.5), virtually all lumbar DRG cells express TrkC mRNA and many require NT-3 and TrkC signaling for survival. In contrast, although many lumbar DRG cells also express TrkA at E11.5, there is little survival dependence on TrkA signaling. By E13.5, most lumbar DRG cells have downregulated TrkC mRNA. The onset of survival dependence on NGF and TrkA-signaling is concurrent and of equal magnitude at E13.5, demonstrating that NT-3 alone does not support DRG neurons via TrkA, nor can NT-3 compensate for the loss of NGF. We conclude that many murine DRG cells require NT-3 activation of TrkA is unimportant to these early NT-3 survival-promoting actions. We suggest that the discrepancy in cell loss between NT-3(-/-) and trkC(-/-) mutants is attributable to the ability of NT-3 to support DRG neurons via TrkA in the artificial situation where TrkC is absent.

Animals↗
PubMed1996

Dorsal root ganglion neurons require functional neurotrophin receptors for survival during development.

Neurotrophins are the most profound known regulators of survival in the developing peripheral nervous system. Within dorsal root ganglia, the signalling receptors for the different members of the neurotrophin family are distributed in distinct patterns suggesting regulation of different functional classes of sensory neurons. Abnormalities observed in neurotrophin receptor mutant mice have confirmed this idea. Both trkA (-/-) and trkC (-/-) mice have striking neurological defecits referrable to subpopulations of DRG neurons which have distinct axon projections in the periphery. These results thus generalize concepts of dependence on target-derived factors based on extensive work with the prototypical neurotrophin, nerve growth factor. Further analysis of these animals also provides evidence for more complex developmental mechanisms including dependence on locally synthesized neurotrophins at early developmental stages and plasticity of neurotrophin receptor expression.

Animals↗
PubMed1996

Nerve growth factor regulates the expression of brain-derived neurotrophic factor mRNA in the peripheral nervous system.

Neurotrophins are profound regulators of neuronal survival in the developing peripheral nervous system and are synthesized by peripheral neurons themselves both during development and in maturity. Neuronal neurotrophin expression may be importantly related to survival of mature neurons, both in normal and pathological states. We show here that brain-derived neurotrophic factor (BDNF) gene expression in dorsal root ganglia is strongly stimulated in vivo by another neurotrophin, nerve growth factor (NGF). Furthermore, colocalization studies show that many BDNF-expressing sensory neurons also express trk A, the high-affinity NGF receptor. These results demonstrate a novel regulatory mechanism for neurotrophin gene expression and suggest a paracrine function for neurotrophins in mature animals.

Animals↗
PubMed1996

Focal expression of glial cell line-derived neurotrophic factor in developing mouse limb bud.

Glial cell line-derived neurotrophic factor (GDNF) is known to support the survival of motoneurons in vitro and in vivo, as well as subpopulations of sensory neurons in vitro. To clarify the mechanisms by which GDNF supports these neurons, we examined the patterns of GDNF mRNA expression in relation to motor and sensory axons during early stages of mouse development. Between embryonic days (E) 10 and 12, a time when motor and sensory axons are entering the periphery, GDNF mRNA is expressed at high levels in a restricted region in proximal limb buds where axons converge and enter the limb. At later ages (E14-16), GDNF mRNA was detected in non-neuronal cells along peripheral nerve, in dermis, and in some muscles. To characterize cells that express GDNF in the proximal limb, GDNF expression in the forelimb was compared to expression patterns of two markers of muscle, Pax 3 and myogenin, as well as with the pan neurotrophin receptor (p75) which is expressed by Schwann cell precursors. We show that expression of GDNF in the proximal limb bud at E11-12 does not correlate with markers of muscle or Schwann cell precursors, which supports the idea that GDNF is expressed by mesenchymal cells in this region. Our results suggest that GDNF expression in proximal limb buds may function as a transient survival factor, particularly for motor neurons, before they reach their final targets. GDNF expression in muscle and dermis at later stages suggests that GDNF may have additional functions as motor and sensory neurons mature.

Animals↗
PubMed1996

BAX is required for neuronal death after trophic factor deprivation and during development.

Members of the BCL2-related family of proteins either promote or repress programmed cell death. BAX, a death-promoting member, heterodimerizes with multiple death-repressing molecules, suggesting that it could prove critical to cell death. We tested whether Bax is required for neuronal death by trophic factor deprivation and during development. Neonatal sympathetic neurons and facial motor neurons from Bax-deficient mice survived nerve growth factor deprivation and disconnection from their targets by axotomy, respectively. These salvaged neurons displayed remarkable soma atrophy and reduced elaboration of neurities; yet they responded to readdition of trophic factor with soma hypertrophy and enhanced neurite outgrowth. Bax-deficient superior cervical ganglia and facial nuclei possessed increased numbers of neurons. Our observations demonstrate that trophic factor deprivation-induced death of sympathetic and motor neurons depends on Bax.

Animals↗
PubMed1996

Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.

The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.

Animals↗
PubMed1995

Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections.

Investigations into the biological actions of nerve growth factor (NGF) have shown that dorsal root ganglion (DRG) neurons subserving nociception require NGF for survival and maintenance of phenotype. This discovery suggests that the signaling NGF receptor, TrkA, can be used as a marker for nociceptive neurons. In this study, we have used antibodies to TrkA, in conjunction with cell biological markers that show a restricted distribution in the DRG, to further characterize subsets of DRG neurons that are dependent upon NGF. Staining for TrkA labeled small and medium-sized neurons that composed 47% of all neurons in thoracic ganglia. Double-labeling with antibodies to the high molecular weight neurofilament protein (NFH), a marker for neurons with myelinated axons, demonstrated that TrkA staining is found in only a small subset of myelinated neurons. Surprisingly, many DRG neurons were not labeled by either TrkA or NFH. These neurons had small soma areas, contained the intermediate filament protein peripherin, and were labeled by the lectin BSI, identifying them as neurons likely to have unmyelinated axons. In addition, small TrkA-negative neurons were extensively labeled by antibodies to the intermediate filament protein alpha-internexin, the delta isoform of protein kinase C, and by the BSI isolectin BSI-B4. In order to assess the potential functions of TrkA-negative small neurons, we examined their projections to the dorsal horn of the spinal cord. TrkA-immunoreactivity in the spinal cord was restricted to lamina I and the outer region of lamina II (IIo), similar to staining for calcitonin gene-related peptide. In contrast, the central projections of TrkA-negative neurons, as visualized by BSI-B4 staining, were particularly dense in lamina IIi. Our results suggest that TrkA-expressing and non-TrkA-expressing small neurons compose functionally distinct populations of DRG neurons.

Animals↗
PubMed1995

The guidance molecule semaphorin III is expressed in regions of spinal cord and periphery avoided by growing sensory axons.

The protein collapsin was purified from chick brain on the basis of its ability to inhibit sensory neuron growth cones, implicating this molecule in sensory axon guidance (Luo et al. [1993] Cell 75:217-227). To examine the relationship between collapsin and sensory axon growth, we examined the pattern of mRNA expression of collapsin's mammalian paralogue, Semaphorin III (Sema III), and compared it to dorsal root ganglion (DRG) axon pathways in the developing rat embryo. Centrally, DRG axons enter the spinal cord by embryonic (E) 11 and branch into the gray matter by E15 in brachial and thoracic regions. Laminar specific targets are reached by E17. Between E13 and E17, Sema III mRNA is expressed at high levels in the entire ventral half of the spinal cord except the floor plate. This pattern suggests that Sema III may inhibit non-proprioceptive sensory axons from penetrating the ventral spinal cord. Peripherally, sensory axons have entered the anterior sclerotome by E11 at all rostrocaudal levels. At this age, Sema III mRNA is already expressed in the dermamyotome and ventral aspect of the posterior sclerotome, areas which axons pass between but do not penetrate en route to their peripheral targets. From E12 to E15, the axons lengthen and branch into smaller fascicles which extend toward peripheral targets. During this time, Sema III mRNA is expressed by many mesodermal structures surrounding the axon fascicles, with highest levels observed in the dermamyotome, perinotochordal mesenchyme, pelvic girdle, and limb. As development proceeds, Sema III mRNA expression is quickly downregulated before disappearing by birth. Taken together, our results demonstrate that the gene for Sema III is expressed in central and peripheral regions which are avoided by growing DRG axons. These findings are consistent with the idea that Sema III inhibits growth and branching of axons into inappropriate areas during development.

Animals↗
PubMed1995

Sensory afferents show appropriate somatotopy at the earliest stage of projection to dorsal horn.

There is a controversy about the extent to which topographic projections in the CNS are determined by initial guidance of axons as opposed to remodeling during development. We have addressed this issue in the rat dorsal root ganglion (DRG) system because dorsal root axons have a readily demonstrable somatotopy in the dorsal horn of the spinal cord and because DRG neurons will ultimately be favorable for molecular analysis. By labeling sensory axons innervating ventral and dorsal skin with different lipid-soluble tracers, we have found that the somatotopic organization of the cutaneous afferent projection is present at the time dorsal root axons first penetrate the gray matter. Our results thus stand in contrast to those in the rat retinocollicular system where the mature retinotopically ordered projection emerges during the postnatal period through remodeling of an early, diffuse projection.

Afferent Pathways↗
PubMed1995

Development of the primary afferent projection in human spinal cord.

The development of spinal cord circuitry in humans is poorly characterized, primarily because standard anatomical tracers must be actively transported, which requires living tissue. Intensely fluorescent lipid-soluble tracers have largely eliminated this problem, at least for circuits that can be traced over short distances. We have, therefore, used the carbocyanine dye DiI (1,1-dioctadecyl-3,3,3,3,-tetramethyl-indocarbocyanine perchlorate) to study the development of the dorsal root afferent projection to fetal human spinal cord between 8 and 19 weeks of gestation. We show here that the dorsal root afferents enter the gray matter of the spinal cord very early in gestation. By 8 weeks, a few axons have already reached the motor pools. These axons, presumably spindle afferents, traverse the length of the spinal gray matter in fascicles to reach different groups of motor neurons. As development progresses, these axons project to the ventral horn and branch in a restricted area in the intermediate zone as well as in the motor pools. Between 11 and 19 weeks of gestation, axons in the ventral horn elaborate boutons that appear to be in proximity to the motor neuron somata and their proximal dendrites. Other groups of axons penetrate the gray matter of the spinal cord all along the mediolateral extent of the dorsal horn. These axons descend to lamina IV, and then turn upward to terminate in laminae III and IV, arborizing primarily rostrocaudally. The time course of the development of these axons parallels that of the axons projecting to the ventral horn.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗