Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche.

The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell-extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ-olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4-fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus-related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.

Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain.

The major catecholamines-dopamine (DA) and norepinephrine (NE)-are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM2+ cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM2+ cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM2+ cell counts) with their NE levels (r = -0.932; p < 0.001), but not their DA levels (r = 0.440; p = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development.

Interaction between Sec7p and Pik1p: the first clue for the regulation of a coincidence detection signal.

Sec7p, a guanine nucleotide exchange factor, regulates the activation of small Arf GTPases, which function in the formation of distinct classes of transport carriers from the Golgi. The recruitment of a subset of Arf effectors depends on the cooperation between these GTPases and phosphatidylinositol 4-phosphate. Here, we show that the catalytic domain of Sec7p interacts with a conserved region of the Golgi phosphatidylinositol 4-kinase Pik1p. We found that Sec7p and Pik1p as well as its product, colocalize at the late Golgi. Gea1p/Gea2p, an alternative pair of Arf activators, do not bind to Pik1p and function on a different Golgi sub-compartment. Sec7p and Pik1p interact with each other and cooperate in the formation of clathrin-coated vesicles. This interaction reveals a distinct role for Sec7p among the Golgi Arf-GEFs and provides a working model for the coordinated generation of Arf-GTP and phosphatiylinositol 4-phosphate as dual signal for specific recruitment of clathrin coats to the late Golgi.