The last couple of decades have witnessed a tremendous growth in the field of medical research associated with overall health, cardiology, molecular oncology, immunology, neurology and many more aspects. The research outcomes were not only able to elucidate the pathophysiology and the anatomical changes associated with the medical conditions linked with the above said fields, but also revealed many novel drug targets and phenomenon which were unknown until now. One such phenomenon and target which has piqued the curiosity of the researchers is of ‘Neuronal Migration’ and ‘Neuron Navigators’.

Neuronal migration is a crucial step involved in the development of the synaptic circuitry of the brain. The entire process can be briefly described as the shifting of immature neurons from the germinal zones to specific locations with a purpose to make axon-target interactions (Hatten, 2002). Recently, researchers have observed a similar phenomenon to be implicated in the adult neurogenesis wherein the sub-ventricular zone derived neuroblasts move towards the olfactory bulb, a site where they spread radially from the center to periphery until they reach the outer layers of the olfactory bulb (Segarra et al., 2015). Neurons migrate in three stages, leading edge extension, nuclear translocation or nucleokinesis, and trailing process retraction. Leading edge extension can occur at the axon's extremity, via growth cone formation, or from the dendrites, via dendritic tip formation (Rouvroit and Goffinet, 2001). Many critical decisions concerning axon outgrowth and guidance are made in the growth cone, where the microtubule network receives input from the cell exterior and works collaboratively with the actin cytoskeleton to guide axons (Dent and Gertler, 2003).

Leading edge extension or neurite extension requires protrusions which are like growth cone (GC) to migrate away from the cell body which are attached by a growing arrangement of microtubule bundles. The primary function of these bundles is to stabilize the growing neurite and provide the means for transporting the membrane necessary for extension (Dehmelt and Halpain, 2003). This entire process of neurite extension is regulated by numerous proteins, some of which are namely, Reelin, Lis1, DCX, Filamin A, Fukutin, Slit, Disc-1, and +TIP (Ayala et al., 2007; Brose and Tessier-Lavigne, 2000; van de Willige et al., 2016). Nucleokinesis commences with the stabilization of the leading process, often accompanied by a lumping of the proximal end of the neurite. The centrosome, which is normally located ahead of the nucleus, moves into the neurite, followed by the nucleus translocation towards the centrosome (Schaar and McConnell, 2005; Tsai and Gleeson, 2005). Microtubules project from the centrosome back towards the nucleus, enveloping it in a “fork” or “cage”-like structure (Rivas and Hatten, 1995; Xie et al., 2003). Alike leading-edge extension, nucleokinesis is also regulated by various proteins, some of them are SUN domain proteins (SUN1 and SUN2), KASH domain proteins (Syne-1 and Syne-2), Dynein 1, and Kineisn Kif1a (Reiner and Karzbrun, 2020). Lastly, there is trailing process retraction, an aspect that remains sparsely understood and demands further research (Ayala et al., 2007).

Microtubule associated proteins (MAPs) that accumulate at growing microtubule plus ends are known as microtubule (MT) plus end tracking proteins (+TIPs) (Schuyler and Pellman, 2001). When compared to other MAPs, their MT end localization is what sets them apart. Most +TIPs preferentially associate with growing MT ends as opposed to depolymerizing MT ends. Surprisingly, some +TIPs can track shrinking MT ends as well; a phenomenon regarded as “backtracking”. This phenomenon is typical of budding yeast +TIPs (Carvalho et al., 2004; Salmon, 2005), but it has also been observed in Drosophila (Mennella et al., 2005), Xenopus (Brouhard et al., 2008), and mammalian cells (Langford et al., 2006). Multiple proteins exhibiting this behaviour have been identified since the discovery of the first +TIP, CLIP-170 (Perez et al., 1999). The several families of +TIPs that have been identified as of now can be broadly classified as EB family (EB1 EB2, and EB3), CLASP family (CLASP1, CLASP2, and CLASP3), APC family (APC, APC2, and APC11), KIF family (kinesin-14, kinesin-13, and kinesin-6), ACF family (ACF7, ACF7L, and ACF7S), and lastly the TPX2 family (TPX2) (Gouveia and Akhmanova, 2010), all of which have been summarised in Table 1.

The mechanism of action of +TIPs involve binding to the growing end (plus end) of the microtubules and regulating the microtubule dynamics (van Haren et al., 2009). +TIPs have unique binding domains that allow them to bind to the growing ends of microtubules. +TIPs regulate the dynamics of the microtubule cytoskeleton by promoting assembly, stabilizing microtubules, and controlling the overall organization and structure of the microtubule cytoskeleton (Akhmanova and Hoogenraad, 2005). The primary functions of +TIPs are to regulate microtubule dynamics, organize the cytoskeleton and determine its structure, control cell division, regulate cell migration, and transport cargo along microtubules (Akhmanova and Hoogenraad, 2005; Gouveia and Akhmanova, 2010; Ferreira et al., 2014). In addition, +TIPS have emerged as potent microtubule regulators owing to their efficiency to control microtubules and relay their signals during neuronal development and homeostasis (van de Willige et al., 2016).

Prior discussing about the mammalian neuron navigators, it's prudent to mention about their invertebrate homologs. Unc-53 in Caenorhabditis elegans and sickie in Drosophila melanogaster are the invertebrate homologs of the neuron navigators. The first description of navigator phenotype linked to unc-53 came from a 1987 screen for mutations affecting axon and cell movement in Caenorhabditis elegans (Hedgecock et al., 1987). In a different study, sickie was found to be involved in actin control during mushroom body development in the fly brain after being identified by an RNA interference screen in fruit flies that searched for genes related to the immune system (Foley and O'Farrell, 2004; Abe et al., 2014). Owing to the scope of this article, invertebrate navigators have been mentioned briefly here, nevertheless, they have been discussed in elaborate details in another article (see review Powers et al., 2023).

A couple of decades back, during the study to understand the dramatic and complex behaviour of cell migration using Caenorhabditis elegans model, Maes et al. (2002) cloned the neuron navigator - 1(NAV1) gene, which is the mammalian homolog of unc-53, a gene involved in axonal guidance in C. elegans (Maes et al., 2002), and mutations on this gene were previously reported to cause, major axonal guidance defects and affect sex myoblast migration (Hekimi and Kershaw, 1993; Chen et al., 1997). During their study, the researchers cloned cDNA corresponding to two additional loci and termed them as NAV2 gene andNAV3 gene. The protein encoded by unc-53 was later designated “Navigator” because of its role in axon outgrowth and cell migration (Maes et al., 2002). As per the present understanding, navigator proteins are large proteins of ~250 kDa belonging to the AAA+ (ATPases Associated with diverse cellular Activities) group of ATPases that contain a microtubule binding domain at the N-terminus and an AAA ATPase domain at the C-terminus and are a member of mammalian microtubule plus end tracking proteins family (Frickey and Lupas, 2004; van Haren et al., 2009; van de Willige et al., 2016). Members of this superfamily of proteins were shown to be involved in a variety of cellular processes, including protein degradation, peroxisome biogenesis, signal transduction, regulation of gene expression, membrane fusion, microtubule severing, and microtubule-mediated transport (van Haren et al., 2009).

Apart from brain development, all these identified neuron navigators have a vital role to play in the normal physiology such as liver organogenesis, development of heart (Klein et al., 2011; Lv et al., 2022) and under pathological states as well and the same has been discussed in a much elaborate manner further in this article. Furthermore, this review aims to provide its readers with the comprehensive and updated knowledge about the possible implications of neuron navigators in normal physiology and certain pathological states as well. According to the present understanding, the three identified neuron navigator genes namely NAV1, NAV2, and NAV3 are all protein coding genes and are differentially expressed in various cells and organ systems at different ages.