Biomedical subjects

Daniel J Liebl

Publications and source records attributed to Daniel J Liebl.

9 recordsLinked to original sources

PubMed2006

EphrinB3 regulates cell proliferation and survival in adult neurogenesis.

Interactions between ephrins and their receptors have been implicated in many processes during central nervous system development. In the adult, ephrins and Eph receptors have been implicated in controlling cell proliferation and neuroblast migration, although there is no direct evidence for the role of ephrinB3 in these functions. In addition, activation of Eph receptors has been shown to regulate transduction pathways important in cell cycle control as well as cell death. We show that ephrinB3 contributes to the control of cell proliferation and survival in the adult subventricular zone (SVZ). EphrinB3(-/-) mice exhibit a significant increase in dividing cells along the lateral ventricle, and altered expression of proteins involved in cell cycle regulation. Gain-of-function approach by infusing soluble ephrinB3-Fc molecules in ephrinB3(-/-) can suppress cell proliferation to wild type levels. At the same time, ephrinB3 also regulates cell survival as greater numbers of cells die in the SVZ of ephrinB3(-/-) mice. Together, our results suggest that ephrinB3 negatively regulates cell cycle progression and cell apoptosis in the adult subventricular zone.

Animals↗

PubMed2006

Distinct roles for ephrinB3 in the formation and function of hippocampal synapses.

The transmembrane ephrinB ligands and their Eph receptor tyrosine kinases are known to regulate excitatory synaptic functions in the hippocampus. In the CA3-CA1 synapse, ephrinB ligands are localized to the post-synaptic membrane, while their cognate Eph receptors are presumed to be pre-synaptic. Interaction of ephrinB molecules with Eph receptors leads to changes in long-term potentiation (LTP), which has been reported to be mediated by reverse signaling into the post-synaptic membrane. Here, we demonstrate that the cytoplasmic domain of ephrinB3 and hence reverse signaling is not required for ephrinB dependent learning and memory tasks or for LTP of these synapses. Consistent with previous reports, we find that ephrinB3(KO) null mutant mice exhibit a striking reduction in CA3-CA1 LTP that is associated with defective learning and memory tasks. We find the null mutants also show changes in both pre- and post-synaptic proteins including increased levels of synapsin and synaptobrevin and reduced levels of NMDA receptor subunits. These abnormalities are not observed in ephrinB3(lacZ) reverse signaling mutants that specifically delete the ephrinB3 intracellular region, supporting a cytoplasmic domain-independent forward signaling role for ephrinB3 in these processes. We also find that both ephrinB3(KO) and ephrinB3(lacZ) mice show an increased number of excitatory synapses, demonstrating a cytoplasmic-dependent reverse signaling role of ephrinB3 in regulating synapse number. Together, these data suggest that ephrinB3 may act like a receptor to transduce reverse signals to regulate the number of synapses formed in the hippocampus, and that it likely acts to stimulate forward signaling to modulate a number of other proteins involved in synaptic activity and learning/memory.

Animals↗

PubMed2006

Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain.

Agenesis of the corpus callosum (CC) is a rare birth defect that occurs in isolated conditions and in combination with other developmental cerebral abnormalities. Recent identification of families of growth and guidance molecules has generated interest in the mechanisms that regulate callosal growth. One family, ephrins and Eph receptors, has been implicated in mediating midline pathfinding decisions; however, the complexity of these interactions has yet to be unraveled. Our studies shed light on which B-class ephrins and Eph receptors function to regulate CC midline growth and how these molecules interact with important guideposts during development. We show that multiple Eph receptors (B1, B2, B3, and A4) and B-class ephrins (B1, B2, and B3) are present and function in developing forebrain callosal fibers based on both spatial and temporal expression patterns and analysis of gene-targeted knock-out mice. Defects are most pronounced in the combination double knock-out mice, suggesting that compensatory mechanisms exist for several of these family members. Furthermore, these CC defects range from mild hypoplasia to complete agenesis and Probst's bundle formation. Further analysis revealed that Probst's bundle formation may reflect aberrant glial formations and/or altered sensitivity of CC axons to other guidance cues. Our results support a significant role for ephrins and Eph receptors in CC development and may provide insight to possible mechanisms involved in axon midline crossing and human disorder.

Animals↗

PubMed2004

Neurogenesis: is the adult stem cell young or old?

Stem cell biology is one of the most exciting, controversial, and debated fields in science today. It has been suggested that neuronal replacement therapy using stem cell transplants may be one possible answer to a host of neuropathological disorders including spinal cord injury, stroke, and neurodegenerative diseases. Important sources for stem cells include the developing embryo and adult central nervous system, but will these populations of cells exhibit similar behavior and responses to stimuli? This review will discuss some important similarities and differences between the embryonic and adult stem cell, as well as the basis for developing therapeutic approaches for stem cell replacement.

Adult↗

PubMed2004

Ephrins and their receptors: binding versus biology.

Ephrins and Eph receptors play important roles in the development of the central nervous system and peripheral tissues by orchestrating cellular movements, resulting in events such as axonal growth cone guidance, tissue segmentation, and angiogenic remodeling. To understand the role of specific ephrin and Eph receptor interactions, it is important to identify the binding specificity between individual ligand-receptor complexes. To date, a dogma in the field suggests that there may be promiscuous binding within the subclasses of the ephrin family. However, this overlooks and contradicts several binding studies that suggest specificity within each subclass. Although binding studies only provide evidence on the dynamics and strength of protein interactions, they do not indicate whether particular interactions are physiologically relevant. Thus, distribution and gene targeted mutations of ephrins and their receptors can provide critical insights into the relevance of specific ligand-receptors interactions. This review mainly focuses on the B-class family and will evaluate the differences between binding affinities and biological functions, importance of oligomeric interactions, and structural differences and similarities between classes.

Animals↗

PubMed2003

mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and adult mouse central nervous system.

Ephrins and Eph receptors are a family of molecules that have been implicated in axonal pathfinding. A unique feature of B-class ephrins and Eph receptors is their ability to transmit bidirectional signals in both ephrin- and Eph receptor-expressing cells upon cell-cell contact. These signals can lead to cytoskeletal alterations that have been attributed to regulating neuronal growth responses. Examination of gene-target knockout mice has supported this hypothesis, revealing numerous developmental defects in the nervous systems of mice mutant for both B-class ephrins and Eph receptors. To examine the potential scope of action for these genes in the nervous system, we have used in situ hybridization to study the mRNA expression of ephrins (B1, B2, and B3) and Eph receptors (B1, B2, B3, A4) in neonatal and adult mice. We found ephrins and Eph receptors to be expressed throughout the CNS. Expression was observed in the epithelium and migratory regions of the neonate and adult tissues as well as in discrete regions of high plasticity, including the adult olfactory bulb, hippocampus, and cerebellum. These studies suggest additional potential roles for these molecules in the postnatal and adult CNS and will serve as a guide in the detailed evaluation of mutant mice.

Aging↗

PubMed2003

Neurotrophin-3 signaling maintains maturational homeostasis between neuronal populations in the olfactory epithelium.

Neurons within the olfactory system undergo functional turnover throughout life. This process of cell death and compensatory neurogenesis requires feedback between neuronal populations of different developmental ages. We examined the role of NT-3 in this process. NT-3 was localized within both the olfactory bulb and olfactory epithelium. Mice null for NT-3 showed increased numbers of immature neurons, without change in the number of mature neurons. This was due to compensatory alterations in apoptosis of mature and immature neuronal populations. Using a primary olfactory neuronal culture, NT-3 was found to directly activate the PI3K/Akt pathway and indirectly activate the MAPK and PLC pathways. Activated PI3K/Akt promoted mature neuronal survival and induced the release of secondary factors, which activated the MAPK and PLC pathways to reduce neuronal precursor proliferation and inhibit neuronal maturation. These effects of NT-3 serve to maintain homeostasis between neuronal populations within the olfactory epithelium.

Animals↗

PubMed2003

Eph receptor deficiencies lead to altered cochlear function.

Ephrins and Eph receptors are a family of molecules that have been implicated in many developmental processes including neuronal network formation, guidance of cell migration, and axonal pathfinding. These molecules exhibit the ability to send bidirectional signals following ligand-receptor interactions resulting from cell-cell contacts. Gene-targeted knockout mice of B-class ephrins and Eph receptors have been shown to display phenotypic responses that correlate with anatomical defects. For example, disruption of the EphB2 receptor leads to defects of the vestibular system, including pathfinding abnormalities in efferent axons and reduced endolymph production. Such developmental distortions lead to deficiencies in ionic homeostasis and repetitive circling behaviors. The present study demonstrates that B-class ephrins and Eph receptors are expressed in cochlear tissues, suggesting that they may play some role in auditory function. To determine whether ephrins and Eph receptors have a functional role in the peripheral auditory system, distortion-product otoacoustic emission (DPOAE) levels, collected across a broad frequency range, were compared between groups of mice expressing different Eph receptor genotypes. In particular, EphB1 and EphB3 receptor knockout mice exhibited significantly diminished DPOAE levels as compared to wild-type littermates, indicating that these specific Eph receptors are necessary for normal cochlear function.

Aging↗

PubMed2002

Atrial natriuretic peptide type C induces a cell-cycle switch from proliferation to differentiation in brain-derived neurotrophic factor- or nerve growth factor-primed olfactory receptor neurons.

With the discovery of postnatal stem cells within the brain, it has become important to understand how extracellular factors might affect the maturation of neuronal precursors in the postnatal brain. Neurotrophic factors are known to play a role in neuronal development but display pleiotrophic effects, in part because of their physiological interactions with other factors. One factor positioned to interact with neurotrophins in the brains of postnatal animals is atrial C-type natriuretic peptide (CNP). In this study, we used olfactory receptor neurons (ORNs) as a model, because their precursors demonstrate the most robust and functional postnatal neurogenesis of those systems thus far described. We examined the effects of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) and the interactions of these neurotrophins and CNP in postnatal olfactory neuronal precursors. Results obtained using mice with targeted deletion of the gene for BDNF indicated that BDNF is a neuroproliferation-inducing and survival factor for ORN precursors. These roles were confirmed in vitro using primary cultures of ORNs. NGF was found to be a proliferation-inducing factor but not a survival factor. The addition of CNP to either BDNF- or NGF-treated neuronal precursors resulted in an inhibition of proliferation and the promotion of maturation. These effects were accompanied by changes in cell-cycle proteins that suggest possible mechanisms for these effects. Thus, CNP may function in the postnatal brain to regulate the exit from the cell cycle in neuronal precursor cells.

Animals↗