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P Ernfors

Publications and source records attributed to P Ernfors.

At least 37 records · Page 2Linked to original sources
PubMed1998

NT-3 regulates expression of Brn3a but not Brn3b in developing mouse trigeminal sensory neurons.

We have used a quantitative RT-PCR approach to determine the levels of Brn3a and Brn3b POU domain transcription factor mRNAs in the developing mouse trigeminal ganglion from E10 to E18. Using low density neuronal cultures, we have shown that NT-3 can regulate the expression of Brn3a mRNA in trigeminal neurons during the periods that they are differentiating and innervating their peripheral and central targets. In contrast to Brn3a, Brn3b mRNA is expressed at extremely low levels in the early trigeminal ganglion. Trigeminal neurons from early ganglia express low levels of Brn3b mRNA in culture and do not up-regulate Brn3b mRNA in response to a number of growth factors and experimental conditions. However, at later ages, when in vivo levels of Brn3b mRNA are high, FGF2, TGFbeta1 and retinoic acid all up-regulate Brn3b mRNA expression in cultured trigeminal neurons. Since NT-3 regulates the developmental expression of Brn3a, Brn3a may mediate some of the effects that NT-3 exerts on sensory neurons and their progenitors. Similarly, Brn3b may mediate some of the effects that FGF2, TGFbeta1 and retinoic acid have on neurons.

Animals↗
PubMed1998

Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system.

Neuropeptide Y, a 36 amino acid peptide, mediates its biological effects by activating the Y1, Y2, Y5 and Y6 receptors, which are also receptors for the structurally related peptide YY. Different classes of receptors have been suggested to be involved in different neuropeptide Y functions. In this report, we have characterized the developmental regulation and compared the cellular localization of these receptors in the developing and in the adult central and peripheral nervous systems of the mouse. RNase protection assays revealed that Y1, Y2 and Y5 messenger RNAs were expressed very early in spinal cord, brain, cerebellum and dorsal root ganglion development and were often down-regulated at times corresponding to their acquirement of the adult function in neurotransmission. In situ hybridization of the adult brain showed that Y1 was widely expressed, Y2 displayed a more restricted pattern, Y5 was expressed at very low levels and only in a few brain nuclei and Y6 was not expressed. Virtually all areas containing neurons positive for Y5 also expressed Y1, whereas many Y1-positive cells clearly did not express Y5. In contrast, Y2 was not expressed by the neurons expressing Y1 or Y5. These findings suggest that neuropeptide Y signaling in the brain could be mediated by simultaneous Y1 and Y5 activation. Similar results were also obtained in peripheral sensory neurons. Furthermore, our results suggest that neuropeptide Y/peptide YY receptors play an important role in nervous system development and that selective receptor combinations are responsible for signaling the different effects of neuropeptide Y in the peripheral and central nervous systems.

Animals↗
PubMed1998

BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex.

Cajal-Retzius (CR) cells of the cerebral cortex express receptors for the neurotrophin brain-derived neurotrophic factor (BDNF) and downregulate expression of the extracellular matrix protein Reelin during early postnatal development, coincident with the onset of cortical BDNF expression. During this period, mice lacking BDNF have elevated levels of Reelin in CR cells. Acute BDNF stimulation of cortical neuron cultures and overexpression of BDNF in the developing brain of transgenic mice prior to the onset of endogenous production causes a profound, dose-dependent reduction of Reelin expression in CR cells. In addition, overexpression of BDNF produces gaps and heterotopias in the marginal zone and disorganization and aggregation of cortical CR cells and induces several other malformations, including aberrant cortical lamination, similar to the phenotype of reeler mutant mice, which lack Reelin. These results demonstrate a role for BDNF on cortical CR cells and identify Reelin as a direct effector of this neurotrophin during brain development.

Animals↗
PubMed1998

Growth arrest failure, G1 restriction point override, and S phase death of sensory precursor cells in the absence of neurotrophin-3.

More than half of the dorsal root ganglion (DRG) neurons are lost by excessive cell death coinciding with precursor proliferation and cell cycle exit in neurotrophin-3 null mutant (NT-3-/-) mice. We find that in the absence of NT-3, sensory precursor cells fail to arrest the cell cycle, override the G1 phase restriction point, and die by apoptosis in S phase, which can be prevented in vivo by a cell cycle blocker. Uncoordinated cell cycle reentry is preceded by a failure of nuclear N-myc downregulation and is paralleled by the activation of the full repertoire of G1 and S phase cell cycle proteins required for cell cycle entry. Our results provide evidence for novel activity of neurotrophins in cell cycle control and point toward an N-myc sensitization to cell death in the nervous system that is under the control of NT-3.

Animals↗
PubMed1997

Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 complement and cooperate with each other sequentially during visceral neuron development.

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) are crucial target-derived factors controlling the survival of peripheral sensory neurons during the embryonic period of programmed cell death. Recently, NT3 has also been found to act in a local manner on somatic sensory precursor cells during early development in vivo. Culture studies suggest that these cells switch dependency to NGF at later stages. The neurotrophins acting on the developing placode-derived visceral nodose/petrosal (N/P) ganglion neurons are BDNF, NT3, and NT4. To assess their roles in development, we analyzed embryonic development in mice carrying a deletion in each of these genes, or combinations of them, and found that they are essential in preventing the death of N/P ganglion neurons during different periods of embryogenesis. Both NT3 and NT4 are crucial during the period of ganglion formation, whereas BDNF acts later in development. Many, but not all, of the NT3- and NT4-dependent neurons switch to BDNF at later stages. We conclude that most of the N/P ganglion neurons depend on more than one neurotrophin and that they act in a complementary as well as a collaborative manner in a developmental sequence for the establishment of a full complement of visceral neurons.

Animals↗
PubMed1997

Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR.

The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innervation and NT-3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.

Animals↗
PubMed1997

Sympathetic neuron survival and TrkA expression in NT3-deficient mouse embryos.

Several in vitro and in vivo studies have led to the widely accepted view that NT3 is required for sympathetic neuroblast survival, induction of TrkA expression and the acquisition of NGF dependence. However, we show that the number of neurons and the levels of trkA and p75 mRNAs in the superior cervical sympathetic ganglion (SCG) of NT3-/- mouse embryos increase normally up to E16, 2 days after SCG neurons start responding to NGF. At E18 and in the postnatal period, there are significant reductions in the number of SCG neurons and in the levels of trkA and p75 mRNAs. These results show that the neurotrophin survival requirements of SCG neurons do not switch from NT3 to NGF during development and that NT3 is not required for the expression of TrkA and p75 and the acquisition of NGF dependence. Rather, some sympathetic neurons have a late requirement for NT3 at the time when they also depend on NGF for survival. The expression of transcripts encoding catalytic TrkC is negligible at this stage, suggesting that NT3 acts mainly via TrkA.

Animals↗
PubMed1997

Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice.

In the kindling model of epilepsy, repeated electrical stimulations lead to progressive and permanent intensification of seizure activity. We find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mice reflected dampening of the progression from focal to generalized seizures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants spent a considerably longer period of time (13 +/- 3 days) than wild-type mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimulation 4-12 weeks after the 10th grade 5 seizure, kindling was maintained in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expression at 2 h after a generalized seizure in dentate granule cells of the NT-3+/- mice, whereas the seizure-evoked increase in brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels was enhanced. These results indicate that endogenous NT-3 levels can influence the rate of epileptogenesis, and suggest a link between NT-3 and BDNF gene regulation in dentate granule cells.

Animals↗
PubMed1997

Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFR alpha after sciatic nerve lesion in the mouse.

Glial cell line-derived neurotrophic factor (GDNF), first characterized for its effect on dopamine uptake in central dopaminergic neurons, appears to be a powerful neurotrophic factor for motor neurons. GDNF has recently been shown to signal through a multisubunit receptor. This receptor is composed of a ligand-binding subunit, called GDNF receptor alpha (GDNFR alpha), and a signalling tyrosine kinase subunit, Ret. To gain further insight into GDNF function, we investigated the expression of GDNF and its receptors after nerve lesion in adult mice. Analysis of expression in muscle, nerve and spinal cord by RNase protection assay and in situ hydridization revealed that, in adult non-lesioned mice, GDNF mRNA was expressed in the nerve and GDNFR alpha mRNA in the nerve and the spinal cord, while the expression of Ret was restricted to spinal cord motor neurons. After a sciatic nerve crush a rapid increase in GDNF mRNA was observed in the distal part of the nerve and a delayed elevation in the muscle, while GDNFR alpha mRNA was up-regulated in the distal part of the sciatic nerve but not in proximal nerve or spinal cord. The lesion also induced a rapid increase in Ret mRNA expression, but the increase was observed only in spinal cord motor neurons and in dorsal root ganglion neurons. A pattern of expression of GDNF and its receptors similar to that seen after lesion in the adult was detected during embryonic development. Administration of GDNF enhanced sciatic nerve regeneration measured by the nerve pinch test. Taken together, these results suggest that GDNF has an important role during regeneration after nerve damage in the adult.

Animals↗
PubMed1997

Learning deficit in BDNF mutant mice.

Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, processes that are also thought to be involved in the learning of spatial tasks such as the Morris water maze. In order to determine whether BDNF is required for normal spatial learning, mice carrying a deletion in one copy of the BDNF gene were subjected to the Morris water maze task. Young adult BDNF mutant mice were significantly impaired compared with wild-type mice, requiring twice the number of days to reach full performance. Aged wild-type mice performed significantly worse than young wild-type mice and the effect was even more pronounced in the BDNF mutant mice, which did not learn at all. Although there was no difference in mean swimming speed between BDNF mutant and wild-type mice, we cannot exclude the possibility that developmental or peripheral deficits also contribute to the learning deficits in these mice. In situ hybridization and RNase protection analysis revealed that BDNF mRNA expression was indeed decreased in BDNF mutant mice. Furthermore, a pronounced effect of age on BDNF mRNA expression was seen, displayed as both a reduced level of mRNA expression and a reduced or entirely absent layer-specific expression pattern in the cerebral cortex of aged animals. Thus, our data suggest that BDNF expression may be linked to learning.

Age Factors↗
PubMed1997

Limb proprioceptive deficits without neuronal loss in transgenic mice overexpressing neurotrophin-3 in the developing nervous system.

The role of neurotrophin-3 (NT3) during sensory neuron development was investigated in transgenic mice overexpressing NT3 under the control of the promoter and enhancer regions of the nestin gene, an intermediate filament gene widely expressed in the developing nervous system. Most of these mice died during the first postnatal day, and all showed severe limb ataxia suggestive of limb proprioceptive dysfunction. Tracing and histological analyses revealed a complete loss of spindles in limb muscles, absence of peripheral and central Ia projections, and lack of cells immunoreactive to parvalbumin in the dorsal root ganglion (DRG). Despite these deficits, there was no neuronal loss in the DRG of these mice. At birth, transgenic DRG showed increased neuron numbers, and displayed a normal proportion of neurons expressing substance P, calcitonin gene-related peptide and the NT3 receptor trkC. Transgenic dorsal roots exhibited an increased number of axons at birth, indicating that all sensory neurons in transgenic mice projected to the dorsal spinal cord. Despite the absence of central Ia afferents reaching motorneurons, several sensory fibers were seen projecting towards ectopic high levels of NT3 in the midline of transgenic spinal cords. These findings suggest novel roles for NT3 in differentiation of proprioceptive neurons, target invasion and formation of Ia projections which are independent from its effects on neuronal survival.

Animals↗
PubMed1997

Lingual deficits in BDNF and NT3 mutant mice leading to gustatory and somatosensory disturbances, respectively.

A combination of anatomical, histological and physiological data from wild-type and null-mutated mice have established crucial roles for BDNF and NT3 in gustatory and somatosensory innervation of the tongue, and indeed for proper development of the papillary surface of the tongue. BDNF is expressed in taste buds, NT3 in many surrounding epithelial structures. Absence of BDNF in mice leads to severely malformed taste bud-bearing papillae and severe reduction of taste buds, a loss of proper innervation of remaining taste buds and a loss of taste discrimination although not of the suckling reflex per se. In contrast, absence of NT3 leads to a massive loss of somatosensory innervation of lingual structures. These findings demonstrate distinct roles for BDNF and NT3 in the establishment of the complex innervation apparatus of the tongue with non-overlapping roles for the lingual gustatory and somatosensory systems. The distinction between different sensory modalities, being dependent on either BDNF or NT3 may also have clinical implications.

Animals↗
PubMed1996

Neurotrophic factors as pharmacological agents for the treatment of injured auditory neurons.

Mature auditory neurons degenerate in response to a loss of target-derived trophic factors. Neurotrophic factors influence the health and viability of auditory neurons. This suggests that neurotrophic factors can be used as therapeutic agents to prevent neuronal cell death and to initiate repair of damaged neuronal processes in the injured auditory system. Both in vitro and in vivo experiments have been performed to determine which of the vast array of neurotrophic factors affect mature auditory neurons and how they can be delivered to the sites of injury within the auditory system. Neurotrophin 3 was found to be a major survival factor for auditory neurons. Brain-derived neurotrophic factor is a minor survival factor for auditory neurons and nerve growth factor, although not promoting survival, does elicit the repair of neuronal processes. Fibroblast growth factor 2, transforming growth factor beta 1 and ciliary neurotrophic factor function as injury-response factors in the auditory system. Combination of different classes of growth factors has an additive effect on neuronal survival. Growth factors may be able to be delivered to sites of injury within the cochlea by either direct perfusion or gene therapy (e.g. a defective virus expressing a growth factor gene).

Animals↗
PubMed1996

A local action of neurotrophin-3 prevents the death of proliferating sensory neuron precursor cells.

The role of neurotrophin-3 (NT-3) in early development of the dorsal root ganglion was investigated. Excessive cell death in the dorsal root ganglion of mice that carry a deleted NT-3 gene (NT-3-/- mice) preceded the period of programmed cell death, detected by the TUNEL method, and caused a reduction in the number of proliferating precursors without altering the proportion of proliferating cells to total number of neurons. Furthermore, the majority of proliferating cells detected by bromodeoxyuridine incorporation also stained with the TUNEL method. NT-3 mRNA was expressed locally in the embryonic, but not the postnatal dorsal root ganglion. Most cultured early embryonic NT-3-/- neurons died in the absence of exogenous NT-3 as did the wild-type neurons when cultured with NT-3 neutralizing antibodies, suggesting that NT-3 acts locally to prevent the death of proliferating sensory precursor cells during neurogenesis. Thus, NT-3 may inflict constraints on the number of proliferating precursor cells and thereby affect the number of neurons generated during development of the peripheral nervous system.

Animals↗
PubMed1996

Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3.

Hearing is conveyed from the auditory receptors, the hair cells in the organ of Corti, to the brain via the spiral ganglion neurons. Damage or loss of either spiral ganglion neurons or hair cells causes hearing impairment. Such hearing disorders are often permanent and can be caused by therapeutic agents, such as aminoglycoside antibiotics and cisplatin, or by aging, loud sounds, infections and mechanical injury (1). Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrohin family of neurotrophic factors that also include nerve growth factor (NGF) and neurotrophin-4/5 (NT-4), are important in development of the neuronal components of the inner ear. We report here that the loss of target innervation and the degeneration of approximately 90% of the adult spiral ganglion neurons caused by aminoglycoside toxicity can be prevented by infusion of the neurotrophic factor, neurotrophin-3 (NT-3) in the membranous labyrinth in guinea pigs. The potency of NT-3 in protecting spiral ganglion neurons from degenerating suggests that neurotrophins may be useful for the treatment of hearing disorders.

Aminoglycosides↗
PubMed1996

Prenatal and postnatal requirements of NT-3 for sympathetic neuroblast survival and innervation of specific targets.

Postnatal homozygous neurotrophin-3 mutant mice display a loss of about half the sympathetic superior cervical ganglion (SCG) neurons (Ernfors, P., Lee, K.-F., Kucera, J. and Jaenisch, R. (1994a) Cell 77, 503-512; Farinas, I., Jones, K. R., Backus, C., Wang, X. Y. and Reichardt, L. F. (1994) Nature 369, 658-661). We found that this loss is caused by excessive apoptosis of sympathetic neuroblasts leading to a failure to generate a normal number of neurons during neurogenesis. NT-3 was also found to be required postnatally. In Nt-3-/- mice, sympathetic fibers failed to invade pineal gland and external ear postnatally; whereas other targets of the external and internal carotid nerves, including the submandibular gland and the iris, displayed a normal complement of sympathetic innervation. Sympathetic fibers of mice carrying one functional copy of the Nt-3 gene (Nt-3+/- mice) invaded the pineal gland, but failed to branch and form a ground plexus. Cultured neonatal sympathetic neurons responded to NT-3 by neurite outgrowth and mRNA upregulation of the NT-3 receptor, trkC. Exogenously administered NT-3 promoted sympathetic growth and rescued the sympathetic target deficit of the mutant mice. We conclude that NT-3 is required for the survival of sympathetic neuroblasts during neurogenesis and for sympathetic innervation and branching in specific targets after birth.

Aging↗
PubMed1996

Requirement of neurotrophin-3 for the survival of proliferating trigeminal ganglion progenitor cells.

The aim of this study was to identify the physiological role of neurotrophin-3 (NT-3) in the development of trigeminal ganglion sensory neurons. For this purpose we have analysed mice carrying a deletion in the NT-3 gene (NT-3-/- mice). In these mice, by embryonic day (E) 11.25% of the trigeminal ganglion neurons were absent and one day later, approximately 50% were absent, after which no further significant changes were observed. Mice carrying one functional NT-3 gene (NT-3+/- mice) displayed a less severe deficit than that of NT-3-/- mice. Whereas programmed cell death occurred between E12 and E14 in the control mice, pronounced excessive cell death was apparent prior to this in the NT-3-/- mice. The excessive cell death led to a progressive decline in the number of proliferating cells without a significant change in the fraction of dividing cells and total number of neurons, indicating that the neuronal deficit of NT-3-/- mice was caused by cell death of trigeminal ganglion progenitors. Furthermore, the degenerating cells had incorporated BrdU, a nucleotide analogue which labels proliferating cells, and expressed nestin, a marker for progenitor cells. Only rarely were degenerating cells seen to express peripherin, present in postmitotic neurons. These data provide evidence that NT-3 is a survival factor for trigeminal ganglion progenitor cells, and suggests that limiting amounts of NT-3 could influence progenitor cell numbers during gangliogenesis.

Animals↗