The Hidden Side of NCAM Family: NCAM2, a Key Cytoskeleton Organization Molecule Regulating Multiple Neural Functions

Abstract

Although it has been over 20 years since Neural Cell Adhesion Molecule 2 (NCAM2) was identified as the second member of the NCAM family with a high expression in the nervous system, the knowledge of NCAM2 is still eclipsed by NCAM1. The first studies with NCAM2 focused on the olfactory bulb, where this protein has a key role in axonal projection and axonal/dendritic compartmentalization. In contrast to NCAM1, NCAM2’s functions and partners in the brain during development and adulthood have remained largely unknown until not long ago. Recent studies have revealed the importance of NCAM2 in nervous system development. NCAM2 governs neuronal morphogenesis and axodendritic architecture, and controls important neuron-specific processes such as neuronal differentiation, synaptogenesis and memory formation. In the adult brain, NCAM2 is highly expressed in dendritic spines, and it regulates synaptic plasticity and learning processes. NCAM2’s functions are related to its ability to adapt to the external inputs of the cell and to modify the cytoskeleton accordingly. Different studies show that NCAM2 interacts with proteins involved in cytoskeleton stability and proteins that regulate calcium influx, which could also modify the cytoskeleton. In this review, we examine the evidence that points to NCAM2 as a crucial cytoskeleton regulation protein during brain development and adulthood. This key function of NCAM2 may offer promising new therapeutic approaches for the treatment of neurodevelopmental diseases and neurodegenerative disorders.

Involvement of CircRNA Expression Profile in Diabetic Retinopathy and Its Potential Diagnostic Value

“…Interestingly, orosomucoid-1 (ORM1), the host gene of hsa_circ_0001883, is an acute phase response (APR) protein that regulates angiogenesis by stimulating VEGF ( Luo et al, 2015 ). Increasing evidence suggests that retinal neuronal degeneration started in the early stages of DR ( Srinivasan et al, 2017 ; Rolev et al, 2021 ), while hsa_circ_0095008 is spliced from neural cell adhesion molecule 2 (NCAM2) that modulates neuronal morphogenesis and differentiation ( Parcerisas et al, 2021 ), which also indicates that circRNAs play a potential role in the early stages of DR. Moreover, circRNAs mainly exert their regulatory functions as miRNA sponges.…”

Regulation of adult neurogenesis and neuronal differentiation by Neural Cell Adhesion Molecule 2 (NCAM2)

“…The mechanism underlying the effects of NCAM2 are not known. The interaction of NCAM2 with microtubule-associated proteins, such as MAP1B, that also participate in the regulation of neuronal migration has also been described (González-Billault et al, 2005; Kawauchi & Hoshino, 2008; Parcerisas et al, 2020; Parcerisas, Ortega-gascó, et al, 2021).…”

“…Moreover, it has been shown that the overexpression of NCAM1 reduces baseline levels of EGFR, enhancing the EGF-induced receptor down-regulation, and that the depletion of NCAM2 increases the levels of the ErbB2 growth factor receptor (Povlsen et al 2008; Deleyrolle et al 2015). Another possibility is that NCAM2 expression could cause cytoskeletal rearrangements, which are known to influence the neurogenetic process (Compagnucci et al, 2016; Parcerisas et al, 2020; Parcerisas, Ortega-gascó, et al, 2021).…”

“…The mammalian neural cell adhesion molecule (NCAM) family is composed of two members, NCAM1 and NCAM2, sharing a similar structure of 5 immunoglobulin domains and 2 fibronectin type III domains, but presenting different expression patterns, post-transcriptional modifications, and molecular interactions (Pébusque et al 1998; Makino and McLysaght 2010; Parcerisas, Ortega-gascó, et al 2021). NCAM1 has been extensively studied and it has been described to play a role in neuronal migration, neurite development, synaptogenesis, and also in neurogenesis by regulating embryonic and adult neural stem cells (NSCs) (Kiselyov et al 2003; Bonfanti 2006; Angata et al 2007a; Boutin et al 2009; Francavilla et al 2009).…”

“…NCAM2 has two different isoforms: NCAM2.1, with a cytoplasmatic domain, and NCAM2.2, which is GPI-anchored (Von Campenhausen et al 1997; Alenius and Bohm 2003). In the central nervous system (CNS), the functions of NCAM2 have been mainly linked to the regulation of the formation and maintenance of axonal and dendritic biology compartments in the olfactory system (Alenius & Bohm, 2003; Kulahin & Walmod, 2010; Parcerisas, Ortega-Gascó, Pujadas, et al, 2021; Winther et al, 2012), and to the control of neural polarization, neurite outgrowth, dendrite development, and synapse formation and maintenance in the cortex and hippocampus through a complex panel of interactors (Leshchyns’Ka et al, 2015; Parcerisas et al, 2020; Sheng et al, 2015; Parcerisas, Ortega-gascó, et al, 2021). Interestingly, NCAM2 has been associated with different pathologies including Down syndrome, autism, and Alzheimer’s disease (JP et al, 2011; Leshchyns’Ka et al, 2015; Paoloni-Giacobino et al, 1997; Parr et al, 2006; Scholz et al, 2016; Winther et al, 2012).…”