ANALYSIS OF β8 INTEGRIN IN NEUROGENESIS AND NEUROVASCULAR HOMEOSTASIS

Neurogenesis in the adult mouse brain occurs within the subventricular zone (SVZ) of the lateral ventricle. In the SVZ, neural stem cells (NSC) reside in a specialized microenvironment, or vascular niche, consisting of blood vessels and their basement membranes. Most NSCs in the SVZ differentiate into progenitor cells, which further differentiate to generate neuroblasts, which then migrate from the SVZ to the olfactory bulbs (OB) along the rostral migratory stream (RMS). ECM-mediated adhesion and signaling within the vascular niche likely contribute to proper NSC self-renewal, survival, differentiation and neuroblast motility. The mechanisms that control these events are poorly understood. Previous studies from our group and others have shown that loss of the ECM receptor, αvβ8 integrin, in NSCs in the embryonic mouse brain leads to severe developmental vascular defects and premature death. Here, the functions of αvβ8 integrin in the adult brain have been examined using mice that have been genetically manipulated to lack a functional β8 integrin gene. This study reveals that loss of β8 integrin leads to widespread defects in homeostasis of the neurovascular unit, including increased intracerebral blood vessels with enhanced perivascular astrogliosis. Additionally, β8 integrin dependent defects in NSC proliferation, survival, and differentiation, as well as neuroblast migration in the RMS were observed both in vivo and in vitro. The defects correlated, in part, with diminished integrin-mediated activation of TGFβ, an ECM ligand of β8 integrin. Collectively, these data identify important adhesion and signaling functions for β8 integrin in the regulation of neural stem and progenitor cells in the SVZ as well as in neuroblast migration along the RMS in the adult brain.

Wingless activity in the precursor cells specifies neuronal migratory behavior in the Drosophila nerve cord.

Neurons and their precursor cells are formed in different regions within the developing CNS, but they migrate and occupy very specific sites in the mature CNS. The ultimate position of neurons is crucial for establishing proper synaptic connectivity in the brain. In Drosophila, despite its extensive use as a model system to study neurogenesis, we know almost nothing about neuronal migration or its regulation. In this paper, I show that one of the most studied neuronal pairs in the Drosophila nerve cord, RP2/sib, has a complicated migratory route. Based on my studies on Wingless (Wg) signaling, I report that the neuronal migratory pattern is determined at the precursor cell stage level. The results show that Wg activity in the precursor neuroectodermal and neuroblast levels specify neuronal migratory pattern two divisions later, thus, well ahead of the actual migratory event. Moreover, at least two downstream genes, Cut and Zfh1, are involved in this process but their role is at the downstream neuronal level. The functional importance of normal neuronal migration and the requirement of Wg signaling for the process are indicated by the finding that mislocated RP2 neurons in embryos mutant for Wg-signaling fail to properly send out their axon projection.

STAT3 CONTROLS THE NEUTROPHIL MIGRATORY RESPONSE TO CXCR2 AND ITS LIGAND MIP-2 (CXCL2)

Among the first white blood cells to respond to bacterial and fungal infections, neutrophils are produced in the bone marrow, released into circulating blood, and recruited to inflamed tissue. The cytokine granulocyte colony-stimulating factor (G