Cellular/Molecular
Myristoylation and Calcium-Binding Proteins
Alexandra P. Few, Nathan J. Lautermilch, Ruth E. Westenbroek, Todd Scheuer, and William A. Catterall
(see pages 7071-7080)
According to Few et al. this week, myristoylation adds diversity to the modulatory functions of neuronal calcium-binding proteins (nCaBPs). The nCaBPs CaBP1 and visinin-like protein-2 (VILIP-2) differ from calmodulin in two important regards: one of the four calcium-binding EF-hand motifs lacks calcium-binding activity, and, notably, these nCaBPs are myristoylated on their N terminus, thus allowing membrane anchoring. The authors used CaV2.1 channels that underlie P/Q-type calcium currents as their test target. CaBP1 positively shifted voltage-dependent activation and accelerated inactivation when coexpressed with CaV2.1. These effects were not observed with a nonmyristoylated mutant protein and were not dependent on calcium influx. VILIP-2 modulation had opposite consequences, causing calcium currents to inactivate more slowly. In contrast to CaBP1 and VILIP-2, endogenous calmodulin imparts calcium-dependent facilitation of calcium currents, an effect that was blocked by native but not nonmyristoylated CaBP1. Thus myristoylation allows nCaBPs to regulate calcium channels in a calcium-independent manner.
Development/Plasticity/Repair
A Role for Integrin-Linked Kinase in Cortical Lamination
Agnieszka Niewmierzycka, Julia Mills, Rene St-Arnaud, Shoukat Dedhar, and Louis F. Reichardt
(see pages 7022-7031)
The development of the cortex and its lamina is so intricate that it is a wonder that malformations such as lissencephaly are not more common. This week, Niewmierzycka et al. implicate integrin linked kinase (Ilk) in cortical lamination. Ilk links integrin receptors to the cytoskeleton and thus is involved in cell adhesion, migration, and extracellular matrix deposition. Using a cre/lox system, the authors deleted Ilk from the mouse dorsal forebrain. Adult Ilk mutants had severe cortical defects: cells invaded the marginal zone, hypocellular regions expanded into underlying cortex, the cerebral hemispheres were fused, and the hippocampal dentate gyrus had an abnormal, scalloped edge. Importantly, the basal lamina was fragmented, radial glia fibers were disorganized, and Cajal-Retzius cells were displaced. Deletion of Ilk from postmitotic neurons did not produce these defects, implicating glial Ilk in basal lamina assembly. The disruption of integrin-dependent basal lamina formation appears to be the key element leading to the Ilk mutant phenotype.
Immunostaining for laminin shows a smooth layer of basal lamina at the cortical surface and around blood vessels (Control). In the Ilk mutant (Mutant), there is fragmentation of laminin (arrow) and complete absence in some regions at the cortical surface (asterisk). See the article by Niewmierzycka et al. for details.
Behavioral/Systems/Cognitive
Fast Oscillatory Bursts in Pigeon Tectum
Gonzalo Marín, Jorge Mpdozis, Elisa Sentis, Tomás Ossandón, and Juan Carlos Letelier
(see pages 7081-7089)
Neurons of the optic tectum in birds respond to visual stimuli with very fast (500-600 Hz) oscillatory bursts (OBs). This week, Marín et al. track the origin of these bursts using simultaneous intracellular and extracellular recordings from single units in anesthetized pigeons. Many units fired with a sustained pattern that did not match OB firing. However, the firing of a second class of units, the terminals of paintbrush axons, matched the oscillatory bursts. The paintbrush terminals, identified with biocytin injection, originated from neurons of the nucleus isthmi pars parvocellularis (Ipc). Ipc neurons fired in a pattern that was tightly synchronized with tectal OBs in response to visual stimuli. Silencing of the Ipc with lidocaine also blocked tectal OB responses. The authors describe the reciprocal projections between the cholinergic neurons of the Ipc and the tectum as a focused “beam of attention” that can enhance visual saliency.
Neurobiology of Disease
Mice That Feel No Pain
Ken-ichiro Kuwako, Akari Hosokawa, Isao Nishimura, Taichi Uetsuki, Masashi Yamada, Shigeyuki Nada, Masato Okada, and Kazuaki Yoshikawa
(see pages 7090-7099)
This week, Kuwako et al. evaluate mice lacking a paternal copy of the necdin gene (Ndn+m/-p), a maternally imprinted, paternally expressed multifunctional signaling protein. The mice share behavioral and developmental features with Prader-Willi syndrome (PWS), a genomic imprinting-associated developmental disorder caused by absence of paternally expressed genes in chromosomal region 15q11-q12. This region includes the gene for necdin. The authors focused on necdin function in the nerve growth factor (NGF)-dependent development of dorsal ganglion neurons, a site of high necdin expression. Necdin mediated the formation of a stable complex between tropomyosin-related kinase A (TrkA) and p75NTR. In the absence of necdin, phosphorylation of TrkA and subsequent NGF-induced TrkA and mitogen-activated protein kinase signaling were reduced. Consequently, apoptosis increased in dorsal root ganglia, including substance P-expressing neurons that mediate noxious pain. Accordingly, Ndn+m/-p mice displayed a higher tolerance for heat-induced pain, as is also frequent in PWS. The authors speculate that necdin may play an analogous role in brain-derived neurotrophic factor/TrkB signaling in central neurons.
