A phosphatase cascade by which rewarding stimuli control nucleosomal response

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.     

Differential Notch signalling distinguishes neural stem cells from intermediate progenitors

During brain development, neurons and glia are generated from a germinal zone containing both neural stem cells (NSCs) and more limited intermediate neural progenitors (INPs). The signalling events that distinguish between these two proliferative neural cell types remain poorly understood. The Notch signalling pathway is known to maintain NSC character and to inhibit neurogenesis, although little is known about the role of Notch signalling in INPs. Here we show that both NSCs and INPs respond to Notch receptor activation, but that NSCs signal through the canonical Notch effector C-promoter binding factor 1 (CBF1), whereas INPs have attenuated CBF1 signalling. Furthermore, whereas knockdown of CBF1 promotes the conversion of NSCs to INPs, activation of CBF1 is insufficient to convert INPs back to NSCs. Using both transgenic and transient in vivo reporter assays we show that NSCs and INPs coexist in the telencephalic ventricular zone and that they can be prospectively separated on the basis of CBF1 activity. Furthermore, using in vivo transplantation we show that whereas NSCs generate neurons, astrocytes and oligodendrocytes at similar frequencies, INPs are predominantly neurogenic. Together with previous work on haematopoietic stem cells, this study suggests that the use or blockade of the CBF1 cascade downstream of Notch is a general feature distinguishing stem cells from more limited progenitors in a variety of tissues.     

Asymmetric multidimensional scaling of two-mode three-way proximities

An asymmetric multidimensional scaling model and an associated nonmetric algorithm to analyze two-mode three-way proximities (object × object × source) are introduced. The model consists of a common object configuration and two kinds of weights, i.e., for both symmetry and asymmetry. In the common object configuration, each object is represented by a point and a circle (sphere, hypersphere) in a Euclidean space. The common object configuration represents pairwise proximity relationships between pairs of objects for the ‘group’ of all sources. Each source has its own symmetry weight and a set of asymmetry weights. Symmetry weights represent individual differences among sources of data in symmetric proximity relationships, and asymmetry weights represent individual differences among sources in asymmetric proximity relationships. The associated nonmetric algorithm, based on Kruskal’s (1964b) nonmetric multidimensional scaling algorithm, is an extension of the algorithm for the asymmetric multidimensional scaling of one mode two-way proximities developed earlier (Okada and Imaizumi 1987). As an illustrative example, we analyze intergenerational occupational mobility from 1955 to 1985 in Japan among eight occupational categories.