Role of Zeb2/Sip1 in neuronal development

doi:10.1016/j.brainres.2018.09.034

Brain Research

Volume 1705, 15 February 2019, Pages 24-31

https://doi.org/10.1016/j.brainres.2018.09.034 Get rights and content

Highlights

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Mutations in Sip1 cause the Mowat-Wilson syndrome in humans.
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Sip1 controls the formation of the hippocampus.
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Sip1 is important for cell fate switch in the neocortex development.
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Sip1 controls migration of interneurons and is required for the onset of gliogenesis.
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Sip1 is needed for axonal growth and branching.

Abstract

Zeb2 (Sip1, Zfhx1b) is a transcription factor that plays essential role in neuronal development. Sip1 mutation in humans was shown to cause Mowat-Wilson syndrome, a syndromic form of Hirschprung’s disease. Affected individuals exhibit multiple severe neurodevelopmental defects. Zeb2 can act as both transcriptional repressor and activator. It controls expression of a wide number of genes that regulate various aspects of neuronal development. This review addresses the molecular pathways acting downstream of Zeb2 that cause brain development disorders.

Section snippets

Zeb2 structure, expression and interactions

Zeb2 is a member of the small Zeb family of two transcription factors Zeb2 (also known as Sip1 and Zfhx1b) and δ EF1 (Zeb1). A common structural feature of these proteins is the presence of a homeodomain separated by two clusters of “zinc-finger” domains with DNA-binding activity. The alternate name of Zeb1, ‘Sip1’, was given for the protein’s ability to interact with activated SMAD transcriptional co-factors (Sip stands for Smad interacting protein). The SMAD interacting domain was not

Zeb2 haploinsufficiency in humans is associated with Mowat–Wilson syndrome

In humans, large scale deletions on chromosome 2 (chr2q22) were found in patients with syndromic forms of Hirschprung disease. This pathology was later attributed to be due to loss of function of the ZEB2 gene (Wakamatsu et al., 2001). Later, as more human patients with heterozygous ZEB2 deficiency were identified and characterized, this condition was named Mowat–Wilson syndrome (MWS). MWS is characterized by various malformations. The major defects appear in the CNS and PNS. They include

Zeb2 deficient mice as models of MWS

The model for studying the molecular mechanism of MWS is Zeb2 knock-out mouse. The excision of exon 7 of Zeb2 generates a null allele in the mouse by premature termination of the protein caused by a frame shift in exon 8 (Higashi et al., 2002, Van de Putte et al., 2003). The first published Zeb2 knock-out model was generated by flanking exon 7 with loxP sites. The conditional exon 7 deletion was performed via crossing the Zeb2flox mouse to Cre expressing mouse (Ella-Cre) (Higashi et al., 2002).

Zeb2 is essential for neural tube and neural crest formation

Zeb2 plays an important role in neural tube patterning where it regulates a number of key genes. Knockout of Zeb2 leads to failure of neural tube closure, and the absence of a sharp boundary between the neural plate and the rest of the ectoderm (Van de Putte et al., 2003). In the development of the neural crest Zeb2 seems to act by limiting BMP-Smad signaling at the border between epidermal ectoderm and neuro-ectoderm (Hegarty et al., 2013). One of the important Zeb2 downstream targets is

Conclusion

To sum up, Zeb2/Sip1 is an important regulator of neuronal development. Mutations in Zeb2 cause the Mowat-Wilson syndrome in humans, which is characterized, in the first instance, by severe mental retardation, various intellectual disorders, craniofacial abnormalities and also by various defects such as absence of corpus callosum, microcephaly, epilepsy, delayed motor development, Hirschsprung’s disease. Mutation of Zeb2 in the mouse has pleiotropic effect. It is essential for normal

Acknowledgments

This work was supported by a grant from Russian Scientific Foundation (project 15-14-10021).

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ZEB2 alleviates Hirschsprung's-associated enterocolitis by promoting the proliferation and differentiation of enteric neural precursor cells via the Notch-1/Jagged-2 pathway
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Hirschsprung’s-associated enterocolitis (HAEC) is a prevalent complication of Hirschsprung’s disease (HSCR). Zinc finger E-box binding homeobox 2 (ZEB2) and Notch-1/Jagged-2 are dysregulated in HSCR, but their role in HAEC progression remains poorly understood. We aimed to explore the role and underlying mechanism of enteric neural precursor cells (ENPCs) and the ZEB2/Notch-1/Jagged-2 pathway in HAEC development.
Colon tissues were collected from HSCR and HAEC patients. ENPCs were isolated from the HAEC group and stimulated by lipopolysaccharide (LPS). The expressions of ZEB2/Notch-1/Jagged-2 were measured using RT-qPCR and Western blot. Immunofluorescence and cell counting kit-8 assays were performed to assess the differentiation and proliferation of ENPCs. Inflammatory factors were measured by ELISA kits. Co-immunoprecipitation and bioinformatic analysis were used to explore the interaction between ZEB2 and Notch-1. Small interfering RNA and overexpression vectors were used to investigate the role and mechanism of ZEB2 and Notch-1 in regulating ENPCs' proliferation and differentiation during HAEC progression.
We observed increased LPS in the colon tissues of HAEC, with downregulated ZEB2 expression and upregulated Notch-1/Jagged-2 expression. ZEB2 interacts with Notch-1. LPS treatment downregulated ZEB2 expression, upregulated Notch-1/Jagged-2 expression, and induced proliferation and differentiation disorders in ENPCs, which were reversed by the knockdown of Notch-1. Furthermore, overexpression of ZEB2 inhibited Notch-1/Jagged-2 signaling and ameliorated inflammation and dysfunction in LPS-induced ENPCs. Notch-1 overexpression enhanced LPS-induced dysfunction, but this effect was antagonized by the overexpression of ZEB2.
Overexpression of ZEB2 ameliorates LPS-induced ENPCs' dysfunction via the Notch-1/Jagged-2 pathway, thus playing a role in HAEC.
Depicting the molecular features of suicidal behavior: a review from an “omics” perspective
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Background Suicide is one of the leading global causes of death. Behavior patterns from suicide ideation to completion are complex, involving multiple risk factors. Advances in technologies and large-scale bioinformatic tools are changing how we approach biomedical problems. The “omics” field may provide new knowledge about suicidal behavior to improve identification of relevant biological pathways associated with suicidal behavior.
Methods We reviewed transcriptomic, proteomic, and metabolomic studies conducted in blood and post-mortem brains from individuals who experienced suicide or suicidal behavior. Omics data were combined using systems biology in silico, aiming at identifying major biological mechanisms and key molecules associated with suicide.
Results Post-mortem samples of suicide completers indicate major dysregulations in pathways associated with glial cells (astrocytes and microglia), neurotransmission (GABAergic and glutamatergic systems), neuroplasticity and cell survivor, immune responses and energy homeostasis. In the periphery, studies found alterations in molecules involved in immune responses, polyamines, lipid transport, energy homeostasis, and amino and nucleic acid metabolism.
Limitations We included only exploratory, non-hypothesis-driven studies; most studies only included one brain region and whole tissue analysis, and focused on suicide completers who were white males with almost none confounding factors.
Conclusions We can highlight the importance of synaptic function, especially the balance between the inhibitory and excitatory synapses, and mechanisms associated with neuroplasticity, common pathways associated with psychiatric disorders. However, some of the pathways highlighted in this review, such as transcriptional factors associated with RNA splicing, formation of cortical connections, and gliogenesis, point to mechanisms that still need to be explored.
Identification of MMACHC and ZEB2 mutations causing coexistent cobalamin C disease and Mowat-Wilson syndrome in a 2-year-old girl
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Citation Excerpt :
In particular, this gene takes part in the embryonic development of neural tube and neural crest[20-24]. A variety of clinical manifestations of MWS have been reported in both mild and severe cases [25]. In infancy, there are special features: ear creases, skull assumes the circular, thinning hair close, swelling in the neck, a square face, high forehead and uplift, high myopia, strabismus, epicanthus, sunken eyes, big eyes wide nose, saddle nose, nasal tip circle, columella, often with open mouth, upper lip is M shape, prominent chin and narrow triangular.
Cobalamin C (cblC) disease and Mowat-Wilson syndrome (MWS) are rare hereditary diseases. To date, there have been no reports of people suffering from these two genetic diseases, or whether there is any correlation between the two diseases. We reported a 2-year-old girl with both cblC disease and MWS. The patient initially manifested as slow weight gain, hypotonia, broad nasal bridge, high forehead, high palate arch, ear crease, patent ductus arteriosus, atrial and ventricular septal defect and bilateral mild ventriculomegaly in the neonatal period. However, as the baby grew older, the typical facial features became more prominent, and overall developmental delays were noted at the subsequent follow-up, with the motor and cognitive development significantly lagging behind that of other children of the same age. At 26 days old, laboratory tests revealed remarkably elevated levels of serum homocysteine, C3/C2 and urine organic acid. Whole-exome sequencing detected compound heterozygous variants in MMACHC, including one previously reported mutation [c.609G > A (p.W203X) and a novel missense mutation[ c.643 T > C (p.Y215H)]. The computer simulations of the protein structure analysis of the novel missense mutation showed the variant p.Y215H replaced a neutral amino acid with a strongly basic lysine, which broken the local structure by changing the carbon chain skeleton and decreasing the interaction with adjacent amino acid. This is expected to damage the utilization of vitamin B12 and influence the synthesis of AdoCbl and MeCbl, contributing to its pathogenicity. Thus, clinical and genetic examinations confirmed the cblC disease. Another heterozygous variant in ZEB2 [NM_014795; loss1(exon:2–10)(all); 127901 bp] was detected by whole-exome sequencing. The heterozygous 3.04 Mb deletion in EB2 [GRCH37]del(2)(q22.2q22.3) (chr2:142237964–145274917) was also confirmed by genome-wide copy number variations (CNVs) scan, which was pathogenic and led to the diagnosis of Mowat-Wilson syndrome. The biochemical indicators associated with cblC disease in the patient were well controlled after treatment with vitamin B12 and betaine. Here, a patient with coexisting cblC disease and MWS caused by different pathogenic genes was reported, which enriched the clinical research on these two rare genetic diseases.
The genetic basis of spatial cognitive variation in a food-caching bird
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These are of particular interest given that the hippocampus (and its taxon-specific homologs) is the area of the brain associated with spatial learning and memory.6 These include ROBO1, ROBO2, and SLIT2—genes known for their involvement in axon guidance, brain development, progenitor cell proliferation, and migration28—as well as WNT3A, LEF1, and ZEB2, which are critical for development of the hippocampus.29,30 Additionally, FGF13 is essential for hippocampal neurogenesis in rodents;31 CNTN6 is critical for brain and hippocampus development, and it has been implicated as an autism risk gene;32 BMP2 is known to affect hippocampal function associated with learning and memory;33 and AGAP3 is involved in regulating synaptic strength associated with learning and memory.34
Spatial cognition is used by most organisms to navigate their environment. Some species rely particularly heavily on specialized spatial cognition to survive, suggesting that a heritable component of cognition may be under natural selection. This idea remains largely untested outside of humans, perhaps because cognition in general is known to be strongly affected by learning and experience.1, 2, 3, 4 We investigated the genetic basis of individual variation in spatial cognition used by non-migratory food-caching birds to recover food stores and survive harsh montane winters. Comparing the genomes of wild, free-living birds ranging from best to worst in their performance on a spatial cognitive task revealed significant associations with genes involved in neuron growth and development and hippocampal function. These results identify candidate genes associated with differences in spatial cognition and provide a critical link connecting individual variation in spatial cognition with natural selection.
Further delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals
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Citation Excerpt :
Mowat-Wilson syndrome (MWS) is characterized by intellectual disability, typical facial features, microcephaly, epilepsy, and multiple anomalies, including agenesis of the corpus callosum, heart defects, urogenital malformations, and Hirschsprung’s disease [1–4]. It is caused by haploinsufficiency of the ZEB2 gene, mostly associated with de novo large deletions and nucleotide variants leading to premature stop codons or to the synthesis of a defective protein [5]. In rare cases, missense variants impairing ZEB2 function can also be responsible for this condition [6].
Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population.
Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0–4; t2 = 5–12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed.
Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5–13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures.
Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam.
Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.
An early cell shape transition drives evolutionary expansion of the human forebrain
2021, Cell
Citation Excerpt :
ZEB2 was previously shown to be involved in early germ layer specification (Chng et al., 2010; Eisaki et al., 2000; Stryjewska et al., 2017), neural tube morphogenesis (Miyoshi et al., 2006), and neural crest differentiation (Yasumi et al., 2016). In the cortex specifically, ZEB2 has been shown to regulate the timing of cortical laminar fate determination (Epifanova et al., 2019; Parthasarathy et al., 2014; Seuntjens et al., 2009) as well as neocortical axon outgrowth (Srivatsa et al., 2015). ZEB2’s previous identification as the causative gene in Mowat-Wilson syndrome (Mowat et al., 2003) further highlights its importance in human neurodevelopment.
The human brain has undergone rapid expansion since humans diverged from other great apes, but the mechanism of this human-specific enlargement is still unknown. Here, we use cerebral organoids derived from human, gorilla, and chimpanzee cells to study developmental mechanisms driving evolutionary brain expansion. We find that neuroepithelial differentiation is a protracted process in apes, involving a previously unrecognized transition state characterized by a change in cell shape. Furthermore, we show that human organoids are larger due to a delay in this transition, associated with differences in interkinetic nuclear migration and cell cycle length. Comparative RNA sequencing (RNA-seq) reveals differences in expression dynamics of cell morphogenesis factors, including ZEB2, a known epithelial-mesenchymal transition regulator. We show that ZEB2 promotes neuroepithelial transition, and its manipulation and downstream signaling leads to acquisition of nonhuman ape architecture in the human context and vice versa, establishing an important role for neuroepithelial cell shape in human brain expansion.

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ReviewRole of Zeb2/Sip1 in neuronal development

Highlights

Abstract

Section snippets

Zeb2 structure, expression and interactions

Zeb2 haploinsufficiency in humans is associated with Mowat–Wilson syndrome

Zeb2 deficient mice as models of MWS

Zeb2 is essential for neural tube and neural crest formation

Conclusion

Acknowledgments

Curr. Opin. Cell Biol.

Int. J. Biochem. Cell Biol.

Cell Stem Cell

Cytokine Growth Factor Rev.

Prog. Neurobiol.

Curr. Opin. Genet. Dev.

J. Biol. Chem.

Neuron

Genomics

Dev. Biol.

Neuron

Neuron

Dev. Biol.

Neurosci. Lett.

Am. J. Hum. Genet.

Neuron

Dev. Biol.

J. Biol. Chem.

Neuron

The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone

Genes Dev.

Molecular characterisation of ninein, a new coiled-coil protein of the centrosome

J. Cell Sci.

Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease

Hum. Mol. Genet.

Aptamers and their potential to selectively target aspects of EGF, Wnt/beta-catenin and TGFbeta-smad family signaling

Int. J. Mol. Sci.

Four amino acids within a tandem QxVx repeat in a predicted extended alpha-helix of the Smad-binding domain of Sip1 are necessary for binding to activated Smad proteins

PLoS ONE

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype

Am. J. Med. Genet.

FGF dependent regulation of Zfhx1b gene expression promotes the formation of definitive neural stem cells in the mouse anterior neurectoderm

Neural Dev.

Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies

Biochem. Soc. Trans.

Spatial genetic patterning of the embryonic neuroepithelium generates GABAergic interneuron diversity in the adult cortex

J. Neurosci.

Mowat-Wilson syndrome

Orphanet. J. Rare Dis.

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature

Am. J. Med. Genet.

Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis

Proc. Natl. Acad. Sci. U.S.A.

Transcriptional regulator ZEB2 is essential for Bergmann glia development

J. Neurosci.

Review
Role of Zeb2/Sip1 in neuronal development