Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in cerebellar granule cells.

Neuregulin (NRG), a growth and differentiation factor that signals via erbB receptor tyrosine kinases, has been shown to have biological effects in both the CNS and the peripheral nervous system. We report here that erbB4 is expressed in mature cerebellar granule cells, where it appears to be concentrated at the granule cell postsynaptic terminals. We also show that one form of NRG, Ig-NRG, plays a crucial role in aspects of cerebellar granule cell development in vitro. First, Ig-NRG treatment of granule cells in culture selectively induces the expression of the GABA(A) receptor beta2 subunit. This increase in subunit expression is paralleled by an increase in functional GABA(A) receptors. In contrast to its effects on GABA(A) receptor subunit expression, Ig-NRG does not upregulate NMDA receptor N2B and N2C subunit expression. Second, we demonstrate that Ig-NRG also enhances neurite outgrowth from cultured granule cells. Ig-NRG does not, however, act as a survival factor for the granule cells. We have compared the effect of Ig-NRG with the effects of brain-derived neurotrophic factor (BDNF), a neurotrophin that exerts specific effects on granule cells in culture, and found that BDNF does not mimic the effects of Ig-NRG on GABA(A) receptor subunit expression. Our results show that Ig-NRG has specific effects on granule cell development and maturation and may regulate these processes in vivo.

Decrease in occurrence of fast startle responses after selective Mauthner cell ablation in goldfish (Carassius auratus).

A single action potential in one of a pair of reticulospinal neurons, the Mauthner cells, precedes a short-latency electromyographic response of the trunk and tail musculature on the opposite side of the body and a fast startle response in goldfish. It has been postulated that not only the Mauthner cell, but also an array of neurons can trigger or participate in fast startle responses (Eaton et al. 1991). We have selectively ablated the Mauthner cells in goldfish to study how neurons of the brainstem fast startle response network interact. The probability of eliciting a fast startle response was significantly less in fish with double Mauthner cell ablations, as compared to the responsiveness of control fish. The finding that there is a significant decrease in the occurrence of fast startle responses in animals with no Mauthner cells, implies that the Mauthner cell may play a role in triggering the involvement of the other network elements in fast startle responses. We hypothesize that Mauthner cell activation may be important in bringing those reticulospinal neurons that are "primed" by the behavioral context to threshold and provides the basis for studies focused on the interactive nature of the brainstem startle response network.

FOG-2: A novel GATA-family cofactor related to multitype zinc-finger proteins Friend of GATA-1 and U-shaped.

GATA factors are transcriptional regulatory proteins that play critical roles in the differentiation of multiple cell types in both vertebrates and invertebrates. Recent evidence suggests that the biological activities of both mammalian and Drosophila GATA factors are controlled in part by physical interaction with multitype zinc-finger proteins, Friend of GATA-1 (FOG) and U-shaped (Ush), respectively. Here we describe a new FOG-related polypeptide, designated FOG-2, that is likely to participate in differentiation mediated by GATA factors in several tissues. Expression of FOG-2 mRNA differs from that of FOG and is largely restricted to heart, neurons, and gonads in the adult. Somewhat broader expression is evident during mouse embryonic development. Similar to FOG and Ush, FOG-2 protein interacts specifically with the amino finger of GATA factors in the yeast two-hybrid system and in mammalian cells. Remarkably, though FOG-2 is quite divergent from FOG in its primary sequence, forced expression of FOG-2 rescues terminal erythroid maturation of FOG-/- hematopoietic cells. Thus, members of the FOG family of cofactors share highly specific association with GATA factors and are substantially interchangeable with respect to some aspects of function in vivo. The interaction of GATA and FOG family members constitutes an evolutionarily conserved paradigm for transcriptional control in differentiation and organogenesis.

Neuregulin and erbB receptors play a critical role in neuronal migration.

The migration of neuronal precursors along radial glial fibers is a critical step in the formation of the nervous system. In this report, we show that neuregulin-erbB receptor signaling plays a crucial role in the migration of cerebellar granule cells along radial glial fibers. Granule cells express neuregulin (NRG), and radial glia cells express erbB4 in the developing cerebellum and in vitro. When the glial erbB receptors are blocked, neurons fail to induce radial glia formation, and their migration along radial glial fibers is impaired. Moreover, soluble NRG is as effective as neuron-glia contact in the induction of radial glia formation. These results suggest that the activation of glial erbB4 by NRG is an early critical step in the neuronal migration program.

Organelle motility and metabolism in axons vs dendrites of cultured hippocampal neurons.

Regional regulation of organelle transport seems likely to play an important role in establishing and maintaining distinct axonal and dendritic domains in neurons, and in managing differences in local metabolic demands. In addition, known differences in microtubule polarity and organization between axons and dendrites along with the directional selectivity of microtubule-based motor proteins suggest that patterns of organelle transport may differ in these two process types. To test this hypothesis, we compared the patterns of movement of different organelle classes in axons and different dendritic regions of cultured embryonic rat hippocampal neurons. We first examined the net direction of organelle transport in axons, proximal dendrites and distal dendrites by video-enhanced phase-contrast microscopy. We found significant regional variation in the net transport of large phase-dense vesicular organelles: they exhibited net retrograde transport in axons and distal dendrites, whereas they moved equally in both directions in proximal dendrites. No significant regional variation was found in the net transport of mitochondria or macropinosomes. Analysis of individual organelle motility revealed three additional differences in organelle transport between the two process types. First, in addition to the difference in net transport direction, the large phase-dense organelles exhibited more persistent changes in direction in proximal dendrites where microtubule polarity is mixed than in axons where microtubule polarity is uniform. Second, while the net direction of mitochondrial transport was similar in both processes, twice as many mitochondria were motile in axons than in dendrites. Third, the mean excursion length of moving mitochondria was significantly longer in axons than in dendrites. To determine whether there were regional differences in metabolic activity that might account for these motility differences, we labeled mitochondria with the vital dye, JC-1, which reveals differences in mitochondrial transmembrane potential. Staining of neurons with this dye revealed a greater proportion of highly charged, more metabolically active, mitochondria in dendrites than in axons. Together, our data reveal differences in organelle motility and metabolic properties in axons and dendrites of cultured hippocampal neurons.

Comparative studies on the Mauthner cell of teleost fish in relation to sensory input.

Most physiological and behavioral studies of the Mauthner cells have used the goldfish and a few other fish from the superorder Ostariophysi, series Otophysi (= otophysans). We first provide some background and recent findings on the Mauthner cells of otophysan fish and then compare this information to that known about the Mauthner cells in certain non-otophysan fish. These comparisons are meant to provide the impetus for a comparative approach to understanding the role of the Mauthner cells in behavior.