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Role of engrailed homeobox 2 (EN2) gene in the development of the cerebellum and effects of its altered and ectopic expressions

Abstract

Background

Morphological organization, folial pattern formation and establishment of the neural circuitry within the cerebellum are the important events taking place during the development of the cerebellum. Expression of engrailed homeobox 2 (EN2) gene plays an essential role in taking place of these events in the developing cerebellum.

Main body

A search was performed by following the PRISMA guidelines to review the role of the EN2 gene in the development of the cerebellum. Human and animal in vivo and in vitro studies showed that expression of the EN2 gene maintains the normal development of the cerebellum, morphological organization, cerebellar foliation, fissure formation, establishment of the afferent topography, molecular pattern formation and patterned gene expression in the developing cerebellum. Altered expression of the EN2 gene changes the morphology and folial pattern of the cerebellum, whereas its activation rescues these defects. EN2 gene polymorphism is reported as a susceptible cause for autism spectrum disorder (ASD). Ectopic expression of EN2 gene may result cancer and it also may play anti-oncogenic role depending on the organ of its expression.

Conclusion

Expression of the EN2 gene is essential for the normal development of the cerebellum. Its altered expression results deformed cerebellum, polymorphysm is associated with autism and ectopic expression may results cancer.

Background

Engrailed homeobox 2 (EN2) is a member of homeobox containing engrailed gene family. It is located in band 7q36.3 of human chromosome 7 within 155,458,129–155,464,831 forward strand. It consists of 3395 base pairs with 2 exon counts. In mice, it is located on chromosome 5. It is a protein encoding gene and expressed during the development of the cerebellum [1].

The human genome project reveals 16 major classes of more than hundred homeobox, 180 base pairs of DNA sequence, containing genes. Homeobox containing genes encode homeodomain protein, a structural motif that binds to DNA and regulates gene expression [2]. For the induction of the EN2 gene, there is an expression of zinc finger of the cerebellum protein family member 1 (Zic1). Zic1 is activated after inhibition of bone morphogenetic protein (BMP) signaling by Noggin or Chordin. Zic1 and other zinc finger of the cerebellum (Zic) proteins synergize with other factors to activate expression of wingless related integration site family member 1 (Wnt1) and other wingless related integration site (Wnt) genes. Wnt proteins activate the expression of the EN2 gene. Whereas, wingless related integration site family member 3a (Wnt3a) protein may act via a Zic1-independent pathway. Another alternate pathway, by which EN2 gene expression is activated, may involve fibroblast growth factor 8 (Fgf8) signaling [3].

Foldings of the outer surface of the cerebellum during its development result in the formation of folia and they are separated by fissures. Folia and fissures are the structural unit of the cerebellar lobules in a mediolateral pattern extended from the vermis to the cerebellar hemispheres. Further, neural connections of the cerebellum are distinct region wise [4]. About 101 billion granule cells, 30.5 million purkinje cells and 4 billion of the rest of the neurons are accommodated within the cerebellum by establishing cerebellar circuitry for maintaining the functional integrity of the cerebellum [5].

The cascades of genes are expressed for the development of the cerebellum and it is essential to understand the role played by each of these genes. Morphological pattern, formation of the folia, fissures and neural circuitry of the cerebellum is regulated by the expression of a certain gene. Engrailed homeobox 1 and 2 (EN1/2) are homologs of segmentation gene engrailed homeobox (EN) [6]. EN2 mutation or altered expression may cause abnormal morphology of the cerebellum [4, 7]. This review highlighted the role of the EN2 gene in the development of the cerebellum and the outcomes of its altered and ectopic expression.

A search was performed in the Pubmed and Google Scholar databases by using the following descriptors: “(Fetus or cerebellum) AND (EN2 gene) AND (Development or cancer or autism)”, without any filters, dated 10 August 2021. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) review protocol was followed for the synthesis of the information as shown in Fig. 1.

Fig. 1
figure 1

Flow of information through the different phases of review

Main text

Animals and human in vitro and in vivo studies showed that the EN2 gene encodes EN2 protein and regulates the development of the cerebellum. The main findings regarding the EN2 gene and its role in the development of the cerebellum are given in Table 1.

Table 1 Role of EN2 gene in the development of the cerebellum

Mutation and ectopic expression of the EN2 gene result in deformed morphology of the cerebellum and cancer of the involved organ as shown in Table 2.

Table 2 Effects of mutation and ectopic expression of EN2 gene

Expression of EN2 gene is required for the morphological organization and pattern formation of the cerebellum (Table 1, Fig. 2)

Fig. 2
figure 2

Normal, ectopic and altered expressions of EN2 gene and outcomes

The vertebrate cerebellum is organized into modules evidenced by the pattern of cerebellar development, structure of the cerebellar circuitry, expression of the specific markers in the specific region and phenotype of the mutation. It has three lobes in the anteroposterior (AP) direction. The anterior lobe lies cranial and posterior lobe lies caudal to the primary fissure, flocculonodular lobe lies caudal to the posterolateral fissure. These morphological subdivisions have functional significance. Spinocerebellar somatosensory function is conserved in the vermal region of the anterior and posterior lobes. The motor planning function of the cerebellum is preserved in the hemispherical part of these two lobes. Vestibular function is associated with the flocculonodular lobe. The vermis and hemispheres of the cerebellum are further subdivided into ten lobules in the anteroposterior axis separated by fissures. Some of the cerebellar structures are organized in a mediolateral (ML) pattern. These include the long axis of the cerebellar folia, deep cerebellar nuclei, climbing and mossy fibers of the cerebellum. Similarly, there is a superficial to deep (SD) arrangement of the cerebellar neurons into four laminae in the fetal life and three laminae after birth in the cerebellar cortex [13].

Animal model studies showed that after the closure of the neural tube, the isthmus (mesencephalic/metencephalic junction) acts as an organizing center for the development of the midbrain and cerebellum. Fgf8 is a main organizing molecule expressed in the isthmus and strong Fgf8 signal activates the Ras-ERK signaling pathway for the development of the cerebellum [8]. Expression of the Wnt1 gene at isthmus stabilizes the expression of the EN2 gene in the metencephalon. EN2 gene is expressed in most of the parts of the developing cerebellum including the outer cortex, white matter and deep cerebellar nuclei. However, the intensity of its expression is different in the different parts of the developing cerebellum. External granular, purkinje and internal granular layers have high intensity of EN2 expression, whereas the molecular layer is devoid of its expression.

Animal model studies showed that the inactivation of the EN2 gene affects the morphology of the lobules of the vermis and cerebellar hemispheres. Some vermal lobules are reduced in size, some are extended more laterally than normal, some are relatively larger than normal and in some regions, hemispheres are fused. Similarly, defective gene results in alteration of positions of fissures in the cerebellar vermis and hemispheres [4, 11]. Purkinje and Bergmann glial fibers form an anchoring unit at the base of each fissure for the proliferation of the granule cells resulting in the formation of folia [9]. Inactivation of the EN2 gene produces defective foliation in the vermal and hemispherical region of the cerebellum, whereas its activation rescues the foliation defects [4, 11]. These events proved that EN2 gene expression is essential in the cells of the cerebellar primordium to regulate the cerebellar foliation, patterning and growth of the folia. Furthermore, the EN2 gene regulates the timing of the formation of the folia and their position along the anteroposterior axis. This gene influences the expression of other genes in the metencephalon to maintain the arrangement and morphology of the cerebellar cortical layers and neurons [4, 7, 11].

EN2 gene expression maintains the cerebellar neural circuitry and morphology of the neurons (Table 1, Fig. 2)

Climbing (olivocerebellar) and mossy (other than olivocerebellar) fibers are the major extrinsic afferents carrying sensory and motor information to the cerebellum. The site of projection of afferent fibers is distinct in the various zones of the cerebellum in the anteroposterior and mediolateral axes and these form distinct parasagittal regions of protein expressions [12]. EN2 mutant animal models studies showed severe disruption of mediolateral topography of the mossy fibers and ectopic projection of these fibers into the neighboring regions. This proved that normal expression of the EN2 gene is essential for the targeted termination of the mossy fibers in a specific region of a lobule of the cerebellum [7]. Another animal model study showed a major reduction of the olivocerebellar fibers in the cerebellum of the mutant EN2 gene. Hence, it can be said that the EN2 gene is responsible for the formation of afferent bands of olivocerebellar and mossy fibers circuitry in the cerebellum [7]. Another study revealed that the EN2 gene is expressed in the precursors of granule cells, deep cerebellar nuclei and neuroglial cells of the cerebellum along with other genes and is responsible for maintaining the shape, number and connections of these neurons [10]. These evidences proved that the expression of the EN2 gene is essential to maintain the cerebellar neural circuitry and morphology of the neurons.

Ectopic expression of EN2 gene (Table2, Fig. 2)

Expression of homeobox containing EN2 gene is a normal phenomenon in the cerebellum, midbrain, medulla, hippocampus and cerebral cortex [24, 26, 27]. However, sometimes it is expressed ectopically in the other body parts. EN2 gene is ectopically expressed in prostate cancer and benign prostatic hyperplasia (BPH). Expression signals are more in the case of prostate cancer than in BPH [35]. Similarly, EN2 gene expression is increased in the case of ovarian tumors particularly in high grade serous ovarian cancer and in platinum resistant tumors [34]. Its expression in the esophagus promotes esophageal squamous cell carcinoma by upregulating the expression of other pro-oncogenic genes [36]. It is also expressed in the human bladder cancer cells which is confirmed by overall sensitivity of 82% and specificity of 75% [31]. Whereas in the kidney, its expression may play an anti-oncogenic role in the oncogenesis and development of clear cell renal cell carcinoma [32]. EN2 gene expression may act as a tumor suppressor gene in non-small cell lung cancer cells and its reduced expression may be associated with the occurrence and development of the non-small cell lung cancer cells [33]. The above studies were confirmed by polymerase chain reaction (PCR), immunofluorescence and immunohistochemical (IHC) tests. The specificity of the antibody used in these studies was validated with western blotting and immunofluorescence tests [32, 34,35,36]. From these findings, it can be said that the biological function of the EN2 gene differs in different types of tumors. Quantification studies of EN2 transcription factor in these tumors may act as a novel cancer biomarker for the effective diagnosis and therapy of cancer, however, for its validation still more researches are recommended.

EN2 gene polymorphism is susceptible for autism spectrum disorder (ASD) (Table 2, Fig. 2)

Genetic and environmental factors are responsible for neurodevelopmental-based ASD. The coordination of more than hundred genes regulates the cortical structure and neural synapses in the brain. There may be involvement of five to fifteen genes for the cause of ASD [14]. No such fundamental idea is established in the association between expression of EN2 gene in cerebellum and ASD. However, studies showed that human EN2 gene is localized to 7q36, an autism susceptibility locus and EN2 gene knockout mice displayed hypoplasia of cerebellum, abnormal cerebellar folia, abnormal cerebellar circuitary and a decrease in the number of purkinje cells which are similar to the features observed in the autistic individuals. These findings support that there is an association between EN2 gene and ASD [14, 16, 28, 29]. Similarly, EN2 gene knockout studies in mice proved that defective EN2 gene results in the loss of inhibitory neurons in the dentate gyrus of the hippocampus, a center for learning and memory. This may be one of the causes associated with ASD [15, 24, 27].

Human gene analysis studies identified polymorphism in the EN2 gene in the case of ASD [23, 25]. Two intronic single nucleotide polymorphisms (rs1861972 and rs1861973) in the EN2 gene are associated with autism [14, 16, 29]. Disruption of EN2 gene showed cerebellar neuropathological changes and alteration in the monoamine system development in the brain that results reduction of serotonin, dopamine and norepinephrine related neurons may leads to ASD [17, 19]. Similarly there is partial loss of GABAergic interneurons in the EN2 knockout cases, accompanied by decrease of brain derived neurotropic factor (BDNF) signaling similar in ASD cases, a crucial determinant of GABAergic differentiation in the brain [16]. From these findings, it can be suspected that defective EN2 gene or EN2 gene polymorphism may be associated with ASD.

Conclusion

EN2 gene is expressed in the cerebellar primordium. It plays an important role in the morphological organization, pattern formation of the cerebellar folia and fissures in the anteroposterior, mediolateral and superficial-deep axes. It also plays a role in the establishment of neural circuitry within the cerebellum. Mutation of the EN2 gene results in deformed cerebellar morphology. Evidence showed that ectopic expression of the EN2 gene in the prostate, ovary, esophagus and urinary bladder may cause cancer. Further studies are recommended to validate the use of EN2 as a diagnostic biomarker or therapeutic targets in the case of cerebellar morphological disorders and cancer.

Availability of data and materials

Not applicable.

Abbreviations

ASD:

Autism spectrum disorder

AP:

Anteroposterior

BDNF:

Brain derived neurotropic factor

BMP:

Bone morphogenetic protein

BPH:

Benign prostatic hyperplasia

DNA:

Deoxyribonucleic acid

EN:

Engrailed homeobox

EN1/2:

Engrailed homeobox 1 and 2

EN2:

Engrailed homeobox 2

GABA:

Gamma aminobutyric acid

IHC:

Immunohistochemical

ML:

Mediolateral

PCR:

Polymerase chain reaction

PRISMA:

Preferred reporting items for systematic reviews and meta-analyses

Ras-ERK:

Rat sarcoma virus- extracellular signal regulated kinase

SD:

Superficial to deep

Wnt:

Wingless related integration site

Wnt1:

Wnt family member 1

Wnt3a:

Wnt family member 3a

Zic:

Zinc finger of the cerebellum

Zic1:

Zic protein family member 1

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Acknowledgements

We acknowledge DC Agarwal, BM Nagpal, BSS Rao, S Hande, N Nayak, K Iyer, S Singh, G Kalthur and BP Powar for their constant support during this study.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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PPP and SGK conceptualized the study, performed the literature search and drafted the original manuscript. CB and SG critically revised it. All authors read and approved the final manuscript.

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Correspondence to Sneha Guruprasad Kalthur.

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Poudel, P.P., Bhattarai, C., Ghosh, A. et al. Role of engrailed homeobox 2 (EN2) gene in the development of the cerebellum and effects of its altered and ectopic expressions. Egypt J Med Hum Genet 23, 95 (2022). https://doi.org/10.1186/s43042-022-00307-8

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Keywords

  • EN2 gene
  • Development of the cerebellum
  • Morphological organization
  • Folial pattern formation
  • Neural circuitry
  • Cancer
  • Autism spectrum disorder