Cellular/Molecular
PDF Differentially Affects Groups of Clock Neurons
Taishi Yoshii, Corinna Wülbeck, Hana Sehadova, Shobi Veleri, Dominik Bichler, Ralf Stanewsky, and Charlotte Helfrich-Förster
(see pages 2597–2610)
The ∼150 clock neurons in Drosophila brain are classified into seven groups based on position, size, protein expression, and function. Some of these groups primarily drive morning activity, whereas others drive evening activity. Interactions among these groups are required to maintain rhythmic activity patterns and molecular oscillations, but these interactions are poorly understood. The neuropeptide pigment-dispersing factor (PDF), which is expressed in the cells that drive morning peak activity, has been proposed to couple the oscillations of different clock neurons. PDF lengthens the period of some neurons, and shortens the period of others. Yoshii et al. have now identified the specific functional groups accelerated and decelerated by PDF. These differential effects of PDF may help adjust circadian activity patterns to seasonal changes in day length. As days lengthen, the morning activity peak in normal flies is accelerated, and the evening peak is delayed. This effect was abolished in PDF-null flies.
Development/Plasticity/Repair
TORC1 and SIK1 Regulate CREB and Dendritic Growth
Shuai Li, Chi Zhang, Hiroshi Takemori, Yang Zhou, and Zhi-Qi Xiong
(see pages 2334–2343)
Long-term synaptic plasticity requires transcription of proteins regulated by cAMP response element-binding protein (CREB). CREB phosphorylation is required for its activation, but it has recently become clear that CREB phosphorylation is not sufficient for CREB-mediated transcription: a cofactor, transducer of regulated CREB (TORC), must also be activated. Li et al. show that TORC1 expression increases in cortical neurons postnatally, when dendrites are growing. Depolarization of cultured cortical neurons with KCl induced dephosphorylation of TORC1. Dephosphorylated TORC1 was translocated from the cytoplasm into the nucleus, where it enhanced CREB-mediated transcription. One CREB target was salt-inducible kinase 1 (SIK1). SIK1 phosphorylated TORC1, reversing nuclear accumulation of TORC1 and thus terminating transcription of CREB target genes. Thus, TORC1 and SIK1 act as on/off switches for CREB-mediated transcription. TORC1 was required for dendritic growth, because overexpression of TORC1 increased dendritic growth in vitro and in vivo, whereas dominant-negative TORC1 or knockdown of TORC1 inhibited dendritic growth.
Behavioral/Systems/Cognitive
TRPM5 and TRPV1 Mediate Metallic Tastes
Céline E. Riera, Horst Vogel, Sidney A. Simon, Sami Damak, and Johannes le Coutre
(see pages 2654–2662)
Divalent salts of iron, zinc, copper, and magnesium taste metallic, but also evoke other sensations, including astringent, salty, and bitter. Riera et al. investigated what receptors mediate these tastes by performing taste tests in wild-type and knock-out mice. Mice chose water containing low concentrations of zinc and iron sulfate over distilled water, but avoided high concentrations of these salts. Mice avoided copper and magnesium sulfate at all concentrations. Attractive properties of zinc and iron were probably mediated by the transient receptor potential (TRP) protein TRPM5, which contributes to sweet, umami, and bitter tastes, and by T1R3, a subunit of sweet and umami receptors: knock-out of these proteins eliminated preferences and increased aversion to zinc and iron. In contrast, knock-out of TRPM5 reduced aversion to magnesium and copper. Knock-out of TRPV1 also reduced aversion to iron and copper salts. Aversion to divalent salts was never eliminated, however, suggesting that other proteins help mediate their tastes.
Neurobiology of Disease
Disruption of Egr2–Nab2 Interaction Reduces Myelination
Robert H. Baloh, Amy Strickland, Elizabeth Ryu, Nam Le, Timothy Fahrner, Mao Yang, Rakesh Nagarajan, and Jeffrey Milbrandt
(see pages 2312–2321)
Charcot–Marie–Tooth (CMT) disease is a group of inherited peripheral neuropathies caused by different genetic mutations and characterized by muscle weakness in the lower limbs. Baloh et al. have created a mouse model of CMT type 4E by knocking in a causative mutation—a point mutation in the transcription factor Egr2—in transgenic mice. Egr2, together with a coregulatory protein, Nab2, is required for expression of genes involved in myelination. The point mutation prevented the association between Nab2 and Egr2, and therefore reduced transcription of Egr2 target proteins. Like patients, mutant mice developed a hypomyelinating neuropathy. The mice appeared normal at birth, but muscle weakness appeared ∼14 d later and progressed rapidly, leading to paralysis and death within 4–7 d. Myelination was reduced, and action potentials slowed and/or failed to propagate to the nerve terminal. Axons did not degenerate, however, indicating that profound motor defects can be produced by myelin loss alone, without secondary axonal degeneration.
In mice expressing mutant Egr2, neuromuscular junctions remained fully occupied. Terminal sprouting of motor axons occurred, consistent with conduction block. Red, Acetylcholine receptors; green, motor axons. See the article by Baloh et al. for details.
