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  • PAK and are ubiquitously expressed in humans and

    2019-07-30

    PAK2 and 4 are ubiquitously expressed in humans and mice and both these genes are required for embryonic development in mice [34]. Pak2 null mice die at embryonic day 8 (E8.0) with prominent defects in vascularization whereas PAK4 ablation causes lethality at E11.5, from heart defects, impairments in the nervous system and vessel formation [35], [36], [37]. Due to embryonic lethality, mice with tissue-specific gene depletion or conditional knockouts have been developed for PAK2 and PAK4. Bone marrow-specific Pak2−/− is associated with macro-thrombocytopenia and abnormal megakaryocyte morphology and function [38]. Conditional depletion of PAK4 in the nervous system produces hydrocephalus and underdeveloped cortical layers [39]. Expression of human and mouse PAK5 mRNA is also restricted to the brain, while PAK6 is expressed mainly in testis, prostate, kidneys as well as in the GW311616 (Fig. 2A). Within different brain areas, group II PAKs are not equally expressed at the protein level. PAK4 was detected only in the pituitary gland in mice [40], whereas PAK5 is abundant in the entire mouse brain with high levels in the cortex, hippocampus, striatum, hypothalamus and cerebellum [40]. The mouse brain is the organ displaying the highest expression of PAK6, while the spinal cord has low amounts of this protein [40]. Both cortex and hippocampus possess elevate expression of PAK6, while striatum and hypothalamus have intermediate amounts. Instead, no PAK6 protein was detected in the mouse cerebellum or pituitary gland [40]. PAK4 and PAK6, but not PAK5, were detected in the basal ganglia both in rats and humans [41]. Altogether, these studies indicate both redundant and specific expression of group II PAKs in the brain. The first characterization of PAK5 and PAK6 knockout mice was published by Nekrasova and colleagues in 2008 [40]. The expression pattern in the brain of PAK5 and PAK6 partially overlaps [40] (Fig. 2A) suggesting possible functional redundancy. Supporting this, both Pak5−/− and Pak6−/− do not exhibit obvious abnormalities, while the double knockout displays several locomotor deficits and learning and memory defects. Interestingly, the highest expression of both PAK5 and PAK6 is in the cortex, hippocampus and striatum, structures that are critically involved in cognitive functions and movement control [40]. Follow-up studies focused on the functional characterization of these mice have identified additional deficits on the single knockout animals including enhanced sensitivity to the stimulant effect of amphetamine in the PAK5−/− and alteration in the body weight in PAK6−/− mice [43], [44]. Although they have been originally discovered in brain tissues, little information is available about PAKs expression pattern in the CNS cells. Based on transcriptome data from Zhang et al. [45], we compared gene expression of the PAK family members in human and mouse whole brain as well as the specific distribution of each member in neurons, astrocytes and microglia/macrophages populations. This analysis reveals that all PAK members are expressed in mouse brain, with PAK1-2-3 and PAK6 displaying the highest levels of expression (Fig. 2B). In humans, PAK1 and PAK3 mRNA are the most abundant in the brain, whereas only PAK5 and PAK6 are detectable out of group II (Fig. 2B). By focusing on the specific expression in nerve cells, we observed that neurons express all PAKs. Indeed, the role of all the six homologues is well established in neuronal cells both in vitro and in vivo [46], [1]. PAK1 and PAK3 are key proteins in the regulation of spine morphology and number and, together with PAK6, where found to promote neurite complexity through their kinase activity [47], [8], (Fig. 3A). Moreover, PAK1 is involved in the modulation of synaptic strength and synaptic vesicle dynamics in neurons (Fig. 3A) [48]. Recently, PAK4 and PAK6 have been proposed to be regulators of gene transcription in brain dopaminergic regions via cAMP response element-binding protein (CREB) and androgen receptor (AR), respectively [41], [49], (Fig. 3A). Glial cells (astroglia and microglia) express the ubiquitous PAK isoforms (PAK1-2-4). Interestingly, PAK6 is present in mouse microglia and two independent studies observed that PAK6 expression in mouse astrocytes considerably rises upon induction of inflammatory states [50], [51] (Fig. 3A). Supporting the idea that PAKs might play a role in astrocytic and microglial cells, multiple lines of evidences associate PAK1 and PAK2 with inflammation and immunity (Fig. 3A). PAK1 and PAK2 are the two most abundantly expressed PAK isoforms in white blood cells, including T lymphocytes, neutrophils, macrophages, and mast cells and, accordingly, Pak1−/− mice display subtle immune defects. Noteworthy, a recent paper demonstrated that PAK4 is expressed in astrocytes and Pak4 knockout in these cells reduces expression of inflammatory cytokines [52], (Fig. 3A).