1. Introduction
The Planar Cell Polarity (PCP) pathway consists of transmembrane proteins, namely Frizzled and Van Gogh-like (Vangl), as well as cytoplasmic proteins, including Dvl and Prickle (Pk). These proteins play a crucial role in driving planar polarization by localizing asymmetrically to the proximal (Vangl and Pk) and distal (Frizzled and Dvl) of epithelial cells [1]. VANGL2 is a mammalian protein homologous to the Drosophila core planar cell polar protein Vang/Strabismus. VANGL2 processes four transmembrane domains, with both the N-terminal and the C-terminus regions located on the cytoplasmic side. The N-terminal region contains two phosphorylated serine/threonine cola, while the C-terminus region contains a coiled-coil domain and a PDZ-binding domain, which can recognize and bind a variety of protein features, such as Dvl (disheveled), Fz (frizzled) and Ror2 (recombinant receptor tyrosine kinase-like orphan receptor 2) [2] [3]. The protein plays a crucial role in various cellular processes such as tissue morphogenesis, asymmetric cell division, localization of epithelial cell appendages, and establishment of asymmetrical cell axes in diverse cell types, including neurons. Its involvement significantly impacts development, proliferation, differentiation, and polarization movements, among other functions [4]. (See Figure 1)
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Figure 1. The Wnt/PCP signaling pathways.
Simplistically, the Fz receptor will activate the DVL, and then activate a series of downstream proteins to modulate the cytoskeletal elements, which drive planar polarization. The role of VANGL2, a transmembrane protein, localizes the cytosolic protein Prickle and puts it proximally [5]. For another, The Fz receptor will aggregate the cytosolic proteins DVL and ANKRD6 distally [6].
2. Methods
First, we collected all the relevant articles about the VANGL2 gene and imported them into the ENDnotes document library. We then classified and screened out all the articles related to the nervous system. We further classified these articles into diseases related to nervous system development, diseases related to co-regulation with other genes, diseases related to neural signal transduction, diseases related to cochlear development, Alzheimer’s disease, tumors and other diseases. Finally, we sorted out the molecular biological basis of related diseases by reading the literature and conducting a summary discussion (See Figure 2).
Figure 2. Methodological contents.
2.1. The Role of VANGL2 in the Nervous System Development and the Occurrence of Related Diseases
VANGL2 plays a crucial role in various aspects of nervous system development, including the embryonic neural tube, the formation of paraganglionic helix at the end of the myelin sheath of the central nervous system, neural crest cell differentiation, brain circuit formation, neurotransmitter release, and the membrane cell cilia and Reissner fiber formation [7] [8] [9] [10]. Neural tube defects (NTDs), also referred to be neural tube malformations, are a group of birth defects resulting from inadequate neural tube formation during the early stages of embryonic development. The primary clinical subtypes of NTDs include anencephaly, spina bifida, and encephalocele [11] [12]. Anencephaly and severe encephalocele frequently result in stillbirths, with only a few cases resulting in live births, albeit with a very limited survival time. Children with spina bifida and mild encephalocele may survive, but unfortunately, there is no cure available, often leading to lifelong disability, manifested as paralysis of the lower limbs, incontinence, and mental retardation, etc, children with spina bifida are also susceptible to hydrocephalus, which often leads to premature mortality. Research conducted on various animal models, including mice, rabbits, zebrafish, and monkeys, have demonstrated a significant correlation between VANGL2 gene abnormalities and the occurrence of neural tube defects, specifically cranial fissures and spina bifida [13] [14] [15] [16]. Furthermore, VANGL2 deficiency can also lead to polarization and morphological disorder of cells within the tail NP (neural plate) and NT (preventing the closure of the neural tube) [17]. As a result, mutations in VANGL2 cause the embryonic neural tube to not close properly [7]. Furthermore, in VANGL2 knockout glial cells, the paraganglionic helix loosens and occurs with cytoskeletal disruption and mislocalization of self-typical adhesion molecules between the inner rings of the helix [8]. Deficiencies in VANGL2 will directly contribute to disorders in neural crest cell differentiation and brain circuit formation. The downregulation of VANGL2 expression leads to a decline in the release of neurotransmitters secreted by autonomic nerves, thereby interfering with the repair and formation of alveolar tissue [9]. Deletion of VANGL2 results in defects in ependymal cell cilia and Reissner fiber formation, as well as idiopathic scoliosis [10]. (See Figure 3)
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Figure 3. The role of Wnt/planar cell polarity signaling in neural tube closure.
(a) The PCP complex in the process of CE is asymmetric, in which the VANG-PK (green) and FZD-DVL (blue) are localized anteriorly and posteriorly, respectively. (b) Neural tube formation is a complicated process. Neurulation starts with the neural plate, the coiling of the neural plate from outside to inside will form the convergent extension (CE) [18]. Outer layer cell intercalation drives CE movements to narrow and extend tissues along the mediolateral line, respectively. (See Figure 4)
β1 integrin, Grhl3Cre, Zic3, Ptk7, VANGL2 exon 1-7 regulate the expression of VANGL2, and then affect the occurrence of NP cells, ependymal cell cilium, Reissner fiber, accessory ganglion helix, neural ridge cell differentiation, brain circuits, and finally lead to neural tube defects. hmmr, N-cadherin, Ap2m1, Dvl, Lady1, Zic3, R-Ras, and VANGL2 work together to establish cell polarity and neuromorphism, ultimately leading to neural tube defects.
Figure 4. VANGL2 and other genes co-regulate neural cell mechanisms.
2.2. VANGL2 and Other Genes Work Together to Regulate Nerve Cells and Their Abnormalities That Lead to the Resulting Diseases
VANGL2 is involved in regulating cell polarity and neuromorphogenesis, alongside a diverse array of other genes. VANGL2 is associated with HMMR (Hyaluronan-mediated motility receptor), N-cadherin, Ap2m1 (adaptor-related protein complex 2, mu 1 subunit), Dvl, Daam1 (disheveled associated activator of morphogenesis 1), Zic3, R-Ras (Ras-related), which collectively exert a synergistic effect in the establishment of cell polarity and neuromorphogenesis. The interruption and elongation of cell polarization in VANGL2 and HMMR mutants prevent RI (radial intercalation), a process crucial for proper neuromorphogenesis. Consequently, the neurodevelopment of these mutants is significantly hindered [19]. VANGL2 and N-cadherin exhibit colocalization and physical interactions within the neural plate, thereby jointly regulating the convergence and expansion of PCP signaling through direct molecular interactions to promote neural tube development [20]. Additionally, VANGL2 has been identified as a negative regulator of axon outgrowth, modulating the molecular binding strength between N-cadherin and actin cytoskeleton [21]. Furthermore, VANGL2 interacts with Ap2m1 in its C-terminal Prickle binding domain, and this interaction mechanism plays a role in neuronal development by inhibiting VANGL2, resulting in a reduction in the production of dendritic branches in the cortical neurons during development [20]. Additionally, VANGL2 inhibits the interaction between Dvl and its downstream effector Daam1, which in turn functionally inhibits the tandemization of Dvl-to-Daam1 genetic information during CE [18] [22]. Moreover, VANGL2 can function in conjunction with R-Ras to transmit signals that control neural tube formation, and VANGL2 binds to inactive R-Ras as an initial mechanism to collectively regulate the expression of signaling pathways [23]. The expression of VANGL2 is various factors, including the regulation of β1 integrins, Grhl3Cre, Zic3, Ptk7, and their genes exons 1-7. The establishment of PCP and the development of β1 integrin play crucial roles in modulating VANGL2 expression, ensuring the convergent elongation of the notochord, maintaining its structural integrity and localization, and ultimately facilitating the development of the nucleus pulposus and the proper alignment of the vertebral body and intervertebral disc. The downregulation of β1 integrin and VANGL2 expression has been implicated in the development of congenital spinal deformities in humans [24]. Grhl3Cre reduced the expression of VANGL2 protein in SE (surface ectoderm) and PNPs (posterior neuropore cells). Reduction in mechanical stress withstood at the main zippering point during the late stage of embryonic closure in Grhl3Cre/+VANGL2Fl/Fl, leading to failure of neural tube closure and subsequent spinal bifida [3]. Additionally, it has also been observed that Grhl3 overexpression interacts with the VANGL2 gene, leading to the development of spina bifida [25]. Furthermore, the deletion of Zic3 disrupts the genetic interaction between the PCP membrane protein VANGL2 and PCP effector genes Rac1 and Daam1, resulting in an increased frequency and severity of neural tube and heart defects [26]. Embryos exhibiting diheterozygous mutations in the Ptk7 and VANGL2 genes are associated with the occurrence of spina bifida [27]. Specifically, the deletion of VANGL2 exon 1-7 has been observed to impact the overall expression of VANGL2 mRNA and its downstream PCP pathway signaling, resulting in neural tube closure failure [28]. It has been reported in the literature that several combinations of two diheterozygous genes involving the PCP core gene VANGL2 and other genes (Sec24b, Sfrp1/Sfrp2/Sfrp5, Dvl3, Scrib, Celsr1, Ptk7, Vangl1) may result in open spina bifida, anencephaly or cranial fissure phenotype. However, only the cranial fissure phenotype is observed in cases of homozygous mutations [29]. Contrarily, VANGL2 serves the dual purpose of inducing the neural tube closure and rescuing NTDs. Additionally, it was found that the core members of Wnt/PCP (RhoA, VANGL2, ickle, Wnt11) effectively rescued Gsc-mediated NTDs [30].
2.3. The Manifestation of VANGL2-Associated Disorders Is Attributed to Abnormal Neural Signaling
VANGL2 is a key player in the assembly of the molecular core complex at neuromuscular synapses, plays an important role in the transmission of Wnt signaling molecules, and acts as a scaffold protein to promote the development of neuromuscular junction (NMJ) [31]. Mutations in this gene result in dysfunction of the motor sensory pathway. Additionally, there exists a genetic interaction between Contactin2 and VANGL2, which collaboratively regulates the caudal migration of facial branchiomotor (FBM) neurons [32]. Wnt4 and Wnt11 collaborate in facilitating the formation of NMJ at the mammalian muscle-nerve junction by activating the canonical and VANGL2-dependent core PCP pathway [33]. Ryk regulates PCP signaling by asymmetrically modulating the distribution of VANGL2 in both the cytoplasm and plasma membrane, thereby leading to the rejection of the Wnt gradient by corticospinal tract (CST) axons [34]. Dysfunctions in nerve signaling factors, such as Wnt4, wat11, and Ryk, result in abnormalities in the VANGL2 protein and cytoskeleton, ultimately leading to the development of neurological disorders.
2.4. The Role of VANGL2 in Cochlear Development and Its Association with the Pathogenesis of Related Diseases
VANGL2, along with Frizzled3 and Frizzled6, play a crucial role in the development of the cochlea by directing the innervation of type II spiral ganglion neurons [35]. Additionally, VANGL2, CELSR1, FZD3, and other core proteins of the PCP pathway collaborate to regulate the polarization organization of the stereociliary tract in auditory and vestibular hair cells, as well as the axonal pathfinding events of these cells. The absence of VANGL2 results in misorientation of the stereociliary bundles, which in turn leads to abnormal cochlear development [36]. Furthermore, the cochlear defects are also associated with wntless deficiency. Wnts and VANGL2 interact to ensure the establishment of histiocyte polarity during development. The absence of VANGL2 significantly exacerbates sensory cell polarization defects [37]. Additionally, genetically heterozygous mice with VANGL2 and Cdh2 mutants exhibit impairments in neural tube closure and cochlear hair cell orientation [19]. The defect in VANGL2 leads to abnormal cochlear development due to synergistic failure with Frizzled3, Frizzled6, CELSR1, FZD3, Wnts, and Cdh2.
2.5. The Insufficiency of VANGL2 Leads to the Emergence of Additional Neurological Disorders
The deficiency of VANGL2 has been implicated in the pathogenesis of Alzheimer’s disease. Additionally, the amyloid precursor protein (APP) interacts physically with the Wnt co-receptors LRP6 and VANGL2 to activate two arms of Wnt signaling, thereby playing a bidirectional role in the regulation of synaptic stability [38]. Furthermore, defects in the VANGL2 gene have been identified as the cause of Glioblastoma multiforme (GBM). Nrdp1 interacts with VANGL2 protein to mediate k63-linked polyubiquitination of the Dishevelled, Egl-10, and Pleckstrin (DEP) domains of the Wnt pathway protein Dvl, thereby hindering the binding of Dvl to phosphatidic acid. The deletion of Nrdp1 in GBM can lead to abnormal activation of vangl-dependent atypical Wnt pathways, thereby facilitating tumor invasion [39]. The VANGL2-ITLN1 fusion is implicated in regulatory networks such as MYCN, ALK, and Wnt/planar cell polarity (PCP) pathways, which are key regulators of neuroblastoma outcome [40]. Increased VANGL2 expression is associated with Bohling-Opitz syndrome, a rare neurodevelopmental disorder characterized by profound intellectual disability, distinct facial features, excessive hair growth, heightened susceptibility to Wilms tumors, and various congenital abnormalities such as cardiac and skeletal defects, leading to the characteristic “BOS posture”. Existing evidence demonstrates that ASXL1 mutant cells exhibit widespread activation of the canonical Wnt signaling pathway at the transcriptional and protein levels, with a particularly notable upregulation of VANGL2 expression [41]. Mutations in the VANGL2 gene are causative factors for hydrocephalus. NHERF1 assembles a ternary complex with Fzd4 and VANGL2 and promotes the translocation of VANGL2 to the plasma membrane, particularly the apical surface of ependymal cells. The formation of this ternary complex disrupts the development of motor cilia, ultimately resulting in hydrocephalus [42].
3. Discussion
Through a comprehensive review and synthesis of the existing literature, we have determined that the VANGL2 gene is pivotal in the development of the nervous system. This includes the development of the embryonic neural tube, the formation of the paraganglionic spiral at the end of the central nervous system myelin sheath, the differentiation of neural crest cells, the formation of brain circuits, the release of neurotransmitters, and the formation of cilia and Reissner fibers in tubular cells. VANGL2 deficiency is closely associated with neural tube defects (NTDs), leading to congenital conditions such as anencephaly, spina bifida, and encephalocele, which can result in severe clinical manifestations like stillbirth, lifelong disability, and premature death. Additionally, VANGL2 deficiency can cause issues such as cell polarization and morphological disorders, glial cell dysfunction, autonomic dysfunction, and scoliosis. VANGL2 interacts with multiple genes (such as hmmr, N-cadherin, Ap2m1, Dvl, Daam1, Zic3, R-Ras, etc.) to jointly regulate cell polarity and neural morphogenesis, and mutations can lead to disrupted cell polarization and neurodevelopmental disorders. For example, mutations in VANGL2 and HMMR—hyaluronan mediated motility receptor Gene prevent radial intercalation, VANGL2 and N-cadherin co-regulate neural tube development, the interaction between VANGL2 and Ap2m1 reduces dendritic branching, VANGL2 inhibits the interaction between Dvl and Daam1, and VANGL2 and R-Ras control neural tube formation. Furthermore, the expression of VANGL2 is regulated by genes such as β1 integrin, Grhl3Cre, Zic3, and Ptk7, and its defects may lead to conditions such as spina bifida and neural tube closure failure. VANGL2 not only plays a key role in neural development but also rescues NTDs through the Wnt/PCP signaling pathway. VANGL2 is critical in neural signal transmission and neuromuscular synapse formation, and its defects can lead to various nervous system-related diseases. VANGL2, along with signaling molecules such as Contactin2, Wnt4, Wnt11, and Ryk, co-regulates neural development, with abnormalities potentially leading to motor sensory pathway disorders and corticospinal tract axon abnormalities. VANGL2 is also involved in cochlear development, and defects can result in abnormal cochlear and hair cell polarization. Moreover, VANGL2 defects are associated with diseases such as Alzheimer’s disease, glioblastoma multiforme, neuroblastoma, Bohling-Opitz syndrome, and hydrocephalus. It influences the normal function and development of the nervous system through interactions with the Wnt signaling pathway and other molecules. Although the role of VANGL2 in nervous system development and related diseases has been extensively studied, research on the treatment of diseases caused by gene defects remains insufficient. We hope that future clinical research will focus on addressing these diseases, ultimately benefiting more patients.
4. Conclusions
VANGL2 deficiency results in abnormal development of the nervous system and is implicated in a variety of related pathologies. These include scoliosis, spina bifida, abnormal nerve conduction, cochlear dysplasia, Alzheimer’s disease, and tumors, among others. Currently, most global treatments for these conditions focus on addressing the symptoms rather than the underlying genetic causes. Therefore, we aspire to advance medical science by developing therapies that target the genetic defects associated with these diseases, thereby providing more fundamental and effective treatments in the future.