Type III neuregulin-1 promotes oligodendrocyte myelination.

The axonal signals that regulate oligodendrocyte myelination during development of the central nervous system (CNS) have not been established. In this study, we have examined the regulation of oligodendrocyte myelination by the type III isoform of neuregulin-1 (NRG1), a neuronal signal essential for Schwann cell differentiation and myelination. In contrast to Schwann cells, primary oligodendrocytes differentiate normally when cocultured with dorsal root ganglia (DRG) neurons deficient in type III NRG1. However, they myelinate type III NRG1-deficient neurites poorly in comparison to wild type cultures. Type III NRG1 is not sufficient to drive oligodendrocyte myelination as sympathetic neurons are not myelinated even with lentiviral-mediated expression of NRG1. Mice haploinsufficient for type III NRG1 are hypomyelinated in the brain, as evidenced by reduced amounts of myelin proteins and lipids and thinner myelin sheaths. In contrast, the optic nerve and spinal cord of heterozygotes are myelinated normally. Together, these results implicate type III NRG1 as a significant determinant of the extent of myelination in the brain and demonstrate important regional differences in the control of CNS myelination. They also indicate that oligodendrocyte myelination, but not differentiation, is promoted by axonal NRG1, underscoring important differences in the control of myelination in the CNS and peripheral nervous system (PNS).

Subventricular zone neuronal progenitors undergo multiple divisions and retract their processes prior to each cytokinesis.

Mitotically active progenitor cells from the anterior portion of the forebrain subventricular zone (SVZa), which give rise throughout life to olfactory bulb interneurons, bear processes and express neuronal markers. To understand how rodent SVZa neuronal progenitors coordinate division and process formation, we used time-lapse videomicroscopy to analyse the proliferative behavior of SVZa progenitors in dissociated cell culture continuously for up to five generations. The cell cycle time of these cultured SVZa cells assessed videomicroscopically (cytokinesis to cytokinesis) was similar to the cell cycle time along the rostral migratory stream in vivo (14-17 h). The relationship between process extension, process retraction and cytokinesis was assessed quantitatively for 120 cells undergoing cytokinesis. Although all of these cells had elaborated processes, virtually all of them completely withdrew their processes prior to cytokinesis. Process withdrawal was rapid and tightly coupled to cytokinesis; 50% of the cells studied initiated process retraction within 30 min of cytokinesis and 96% had begun to withdraw their processes within 60 min of cytokinesis. In SVZa progenitor cell lineages, the sequence of process extension, process retraction and division is repeated over multiple generations. This complete withdrawal of processes prior to division differentiates SVZa progenitor cells from the characteristics reported for several other process-bearing types of neural progenitor cells, including sympathetic neuroblasts, cerebral cortical radial glia, and cerebellar and retinal progenitors. Collectively, our findings indicate that SVZa progenitors employ different cellular mechanisms than other neural progenitors to regulate proliferation and differentiation.

Neuregulin-1 type III determines the ensheathment fate of axons.

The signals that determine whether axons are ensheathed or myelinated by Schwann cells have long been elusive. We now report that threshold levels of neuregulin-1 (NRG1) type III on axons determine their ensheathment fate. Ensheathed axons express low levels whereas myelinated fibers express high levels of NRG1 type III. Sensory neurons from NRG1 type III deficient mice are poorly ensheathed and fail to myelinate; lentiviral-mediated expression of NRG1 type III rescues these defects. Expression also converts the normally unmyelinated axons of sympathetic neurons to myelination. Nerve fibers of mice haploinsufficient for NRG1 type III are disproportionately unmyelinated, aberrantly ensheathed, and hypomyelinated, with reduced conduction velocities. Type III is the sole NRG1 isoform retained at the axon surface and activates PI 3-kinase, which is required for Schwann cell myelination. These results indicate that levels of NRG1 type III, independent of axon diameter, provide a key instructive signal that determines the ensheathment fate of axons.

Dasm1: a receptor that shapes neuronal dendrites and turns on silent synapses?

Recent research suggests that mouse Dasm1, a protein likely to function as a neuronal cell-surface receptor, plays an important role in both shaping the dendritic tree and affecting the fraction of electrically active glutamatergic synapses. This Perspective considers the question of whether Dasm1 is indeed a receptor and the in vivo implications of the reported in vitro effects of Dasm1 on dendrite growth, AMPA receptor distribution, and synapse unsilencing.

Synthesis and structure-activity relationships of isoxazole carboxamides as growth hormone secretagogue receptor antagonists.

A series of isoxazole carboxamide derivatives has been developed as potent ghrelin receptor antagonists. The synthesis and structure-activity relationship (SAR) are described.

Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators.

The SAR at C-5 of the 10-methoxy-2,2,4-trimethylbenzopyrano[3,4-f]quinoline core leading to identification of (-) anti 1-methylcyclohexen-3-yl as the optimum substituent that imparts minimal GR mediated in vitro transcriptional activation while maintaining full transcriptional repression is described. The in vitro profile of these candidates in human cell assays relevant to the therapeutic window of glucocorticoid modulators is outlined.

Regulation of spine morphology and synaptic function by LIMK and the actin cytoskeleton.

Filamentous actin (F-actin) is highly enriched in the dendritic spine, a specialized postsynaptic structure on which the great majority of the excitatory synapses are formed in the mammalian central nervous system (CNS). The protein kinases of the Lim-kinase (LIMK) family are potent regulators of actin dynamics in many cell types and they are abundantly expressed in the CNS, including the hippocampus. Using a combination of genetic manipulations and electrophysiological recordings in mice, we have demonstrated that LIMK-1 signaling is important in vivo in the regulation of the actin cytoskeleton, spine morphology, and synaptic function, including hippocampal long-term potentiation (LTP), a prominent form of long lasting synaptic plasticity thought to be critical to memory formation. Our results provide strong genetic evidence that LIMK and its substrate ADF/cofilin are involved in spine morphology and synaptic properties and are consistent with the notion that the Rho family small GTPases and the actin cytoskeleton are critical to spine structure and synaptic regulation.

Neuregulins: functions, forms, and signaling strategies.

The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review.

Neuregulins and the neuromuscular system: 10 years of answers and questions.

The neuregulins were originally discovered in searches for the acetylcholine receptor-inducing activity (ARIA), glial growth factor (GGF), and a ligand for the oncogene neu (ErbB2/HER2). Neuregulin1 (NRG1)-mediated cell communication is critical in the central and peripheral nervous system, heart, breast, and other organ systems. This review will focus on the functions of NRG1s in the development and maintenance of the neuromuscular system and on the regulation of NRG1 signaling within this system. The roles of NRG1 signaling in the neuromuscular system are far more pervasive than contemplated when neuregulins were discovered 10 years ago. In fact, neuregulin-mediated cell communication plays an essential role in the biology of most components of the neuromuscular system--including motor and sensory neurons, muscle fibers, Schwann cells, and major specializations (neuromuscular synapses, muscle spindles, Golgi tendon organs, and peripheral nerves). It is argued here that while NRG1 proteins are indeed "ARIA" and "GGF", their involvement in regulating synapse-specific transcription and Schwann cell development is more complex than originally proposed. It is also argued that NRG1 isoforms differ in their signaling properties and that these differences tailor specific isoforms for specific signaling tasks; for example, some NRG1 isoforms may be specialized for paracrine signaling and others for juxtacrine signaling. In the first 10 years of neuregulin research there has been much progress in understanding the actions of neuregulins in shaping and maintaining the neuromuscular system. However, major questions, old and new, remain unanswered; and the second 10 years promises to be at least as exciting as the first.

Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice.

In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.