Generation of cat retinal ganglion cells in relation to central pathways

The ganglion cells of the cat retina form classes distinguishable in terms of perikaryal size, dendritic morphology and functional properties. Further, the axons differ in their diameters, patterns of chiasmatic crossing and in their central connections. Here we define, by 3H-thymidine autoradiography, the order of production of cells of each class and relate the order of the 'birthdates' to the known axonal pathways. The ganglion cell classes are produced in broad waves, which overlap as cells are produced first for central then for peripheral retina. Medium-sized cells are produced before the largest cells, and small ganglion cells are produced throughout the period of cell generation. This sequence of cell production relates to the orderly arrangement of axons in the optic tract, and can also be related to the rules of chiasmatic crossing observed for each ganglion cell class.     

The hyh mutation uncovers roles for alpha Snap in apical protein localization and control of neural cell fate

The hyh (hydrocephalus with hop gait) mouse shows a markedly small cerebral cortex at birth and dies postnatally from progressive enlargement of the ventricular system. Here we show that the small hyh cortex reflects altered cell fate. Neural progenitor cells withdraw prematurely from the cell cycle, producing more early-born, deep-layer cerebral cortical neurons but depleting the cortical progenitor pool, such that late-born, upper-layer cortical neurons are underproduced, creating a small cortex. hyh mice carry a hypomorphic missense mutation in the gene Napa encoding soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein alpha (alpha Snap), involved in SNAP receptor (SNARE)-mediated vesicle fusion in many cellular contexts. A targeted null Napa mutation is embryonically lethal. Altered neural cell fate is accompanied by abnormal localization of many apical proteins implicated in regulation of neural cell fate, including E-cadherin, beta-catenin, atypical protein kinase C (aPKC) and INADL (inactivation-no-afterpotential D-like, also known as protein associated with Lin7, or Pals1). Apical localization of the SNARE Vamp7 is also disrupted. Thus, alpha Snap is essential for apical protein localization and cell fate determination in neuroepithelial cells.     

The VASE exon downregulates the neurite growth-promoting activity of NCAM 140.

Axonal growth, guidance and synapse formation are controlled by receptors on neuronal growth cones that can recognize positive and inhibitory cues in the local microenvironment. Four well characterized receptor systems are known that recognize the growth-promoting activities associated with the extracellular matrix and the membranes of cells such as astrocytes, muscle cells and Schwann cells; these are the integrins and the homophilically binding cell adhesion molecules neural-cell adhesion molecule (NCAM), N-cadherin and L1 (refs 5-12). Alternative splicing generates 20-30 isoforms of NCAM and these can also be differentially glycosylated. There are two sites where alternative splicing changes the extracellular structure of membrane-bound NCAM and one of these (the MSD1 region) does not obviously affect function. Here we report that the variable alternatively spliced exon (VASE) in immunoglobulin domain 4 downregulates the neurite outgrowth-promoting activity of NCAM. The high level of VASE expression in the adult central as compared with peripheral nervous system could contribute to the poor regenerative capacity of the former.     

Calcium-dependent enhancement of calcium current in smooth muscle by calmodulin-dependent protein kinase II.

Calcium entry through voltage-activated Ca2+ channels is important in regulating many cellular functions. Activation of these channels in many cell types results in feedback regulation of channel activity. Mechanisms linking Ca2+ channel activity with its downregulation have been described, but little is known of the events responsible for the enhancement of Ca2+ current that in many cells follows Ca2+ channel activation and an increase in cytoplasmic Ca2+ concentration. Here we investigate how this positive feedback is achieved in single smooth muscle cells. We find that in these cells voltage-activated calcium current is persistently but reversibly enhanced after periods of activation. This persistent enhancement of the Ca2+ current is mediated by activation of calmodulin-dependent protein kinase II because it is blocked when either the rise in cytoplasmic Ca2+ is inhibited or activation of calmodulin-dependent protein kinase II is prevented by specific peptide inhibitors of calcium-calmodulin or calmodulin-dependent protein kinase II itself. This mechanism may be important in different forms of Ca2+ current potentiation, such as those that depend on prior Ca2+ channel activation or are a result of agonist-induced release of Ca2+ from internal stores.