Vav3 Is Involved in GABAergic Axon Guidance Events Important for the Proper Function of Brainstem Neurons Controlling Cardiovascular, Respiratory, and Renal Parameters

Abstract

Vav3 is a phosphorylation GDP/GTP exchange factor for Rho/Rac GTPases. Recently, it has been described that Vav3 knockout mice develop hypertension and sympathoexcitation. In this work, we report the neurological cause of this phenotype.

Transcriptional Factor Aryl Hydrocarbon Receptor (Ahr) Controls Cardiovascular and Respiratory Functions by Regulating the Expression of the Vav3 Proto-oncogene

“…1, A and B). Likewise, as in the case of the latter mouse strain (38,40), we detected high blood pressure (Fig. 1, C and E) and tachycardia (Fig.…”

“…2, A and C) and normal thickness of pulmonary arterioles (data not shown). Lack of pulmonary hypertension of Vav3 Ϫ/Ϫ mice has been shown before (38,40). These results indicate that Ahr-and Vav3-deficient mice develop very similar dysfunctions in the respiratory and cardiovascular system.…”

“…Ϫ/Ϫ -like Respiratory and Cardiovascular Phenotype-Vav3-deficient mice display severe defects in breathing cycles and the cardiovascular system (38,40). Given the reduced levels of Vav3 in Ahr Ϫ/Ϫ mice, we surmised that the phenotypes of Ahr-and Vav3-deficient mice could show some overlap.…”

“…4A). In the case of Vav3 Ϫ/Ϫ mice, we have found that axons from GABAergic CVLM neurons do not properly reach the RVLM, leading to loss of inhibitory GABAergic transmission and up-regulation of RVLM-dependent functions (40). To investigate whether a similar defect could be present in Ahr Ϫ/Ϫ mice, we first determined whether Ahr was expressed in the VLM and, if so, whether its knock-out led to alterations in Vav3 expression.…”

“…This gene encodes a tyrosine phosphorylation GDP/GTP exchange factor for Rho/Rac family GTPases that plays important roles in cytoskeletonlinked signaling events activated by transmembrane and/or cytoplasmic tyrosine kinases (36,37). Recent genetic experiments using knock-out mice have revealed that this GDP/ GTP exchange factor is important for cardiovascular homeostasis (38), adequate control of sympathetic activity (38), the timely development of the cerebellum in early postnatal stages (39), and axon guidance events in inhibitory GABAergic cells of the VLM (40), a brainstem region involved in the coordinated control of cardiovascular, respiratory, adrenal, and renal activities (41,42). Cooperating with other Vav family members (Vav1 and Vav2), Vav3 also participates in the development, selection, and antigen responses of lymphocytes (43), the effector functions of other hematopoietic lineages, angiogenesis (43), and axon guidance events (44).…”