Zeb2 regulates the balance between retinal interneurons and Müller glia by inhibition of BMP–Smad signaling

Menuchin-Lasowski, Yotam; Dagan, Bar; Conidi, Andrea; Cohen-Gulkar, Mazal; David, Ahuvit; Ehrlich, Marcelo; Giladi, Pazit Oren; Clark, Brian S.; Blackshaw, Seth; Shapira, Keren E.; Huylebroeck, Danny; Henis, Yoav I.; Ashery‐Padan, Ruth

doi:10.1016/j.ydbio.2020.09.006

Cited by 6 publications

(8 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next took advantage of this information to see whether gorilla organoids could be encouraged to take on a more human-like phenotype by manipulating SMAD signaling. We focused on activation of BMP-responsive SMADs, because this pathway has previously been shown to inhibit EMT (Amarnath and Agarwala, 2017), and ZEB2 can inhibit BMP-responsive SMADs in other neuronal contexts (Menuchin-Lasowski et al, 2020). Application of BMP4 on gorilla organoids when they would normally begin transitioning to tNE cell morphologies led to the appearance of cells with more dilated apical processes (Figure 7I) and enlarged apical contacts (Figures 7J and 7K), reminiscent of human NE cells.…”

Section: Manipulation Of Zeb2 Expression and Downstream Signaling Leads To Interspecies Phenocopymentioning

confidence: 99%

An early cell shape transition drives evolutionary expansion of the human forebrain

Benito-Kwiecinski

Giandomenico

Sutcliffe

et al. 2021

Cell

180

118

View full text Add to dashboard Cite

Summary 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.

show abstract

Section: Manipulation Of Zeb2 Expression and Downstream Signaling Leads To Interspecies Phenocopymentioning

confidence: 99%

An early cell shape transition drives evolutionary expansion of the human forebrain

Benito-Kwiecinski

Giandomenico

Sutcliffe

et al. 2021

Cell

180

118

View full text Add to dashboard Cite

show abstract

“…Collectively, the homozygous Zeb2 -cKO mouse models provided explanations for multiple defective cellular and developmental aspects of MOWS in humans. This was the case for CNS deficiencies, such as brain neuro/gliogenesis and guided migration of forebrain interneurons [ 47 , 64 ], as well as for eye lens malformation and for the resulting imbalance between cell types in the early and late retina [ 77 , 79 , 86 ], neurocristopathies resulting from aberrant craniofacial and ENS, as well as trunk NCCs [ 8 , 59 , 87 ], and reduced pain sensitivity [ 73 , 74 ].…”

Section: Zeb2 and Mowat-wilson Syndrome And Beyondmentioning

confidence: 99%

“…However, this may not necessarily be the single action mechanism regulating ZEB2-Smad interaction at target genes. For example, activated SMAD1/5 and ZEB2 can be found together on their neighboring binding sites in the BMP-induced Id1 promoter, which leads to strong downregulation of such Id1 [ 86 ], hence reflecting the generation of anti-BMP(Smad) activity. This mechanism also explained how ZEB2 can overcome the BMP-mediated inhibition of embryonic CNS myelinogenesis, by directly promoting myelination from oligodendrocyte precursor cells downstream of the crucial OLIG1/2 TFs: here BMP-SMAD induced genes, which activate genes that inhibit myelinogenesis, are then repressed via ZEB2.…”

Section: Zeb2 Gene and Protein Organizationmentioning

confidence: 99%

“…In a follow-up study by the team of R. Ashery-Padan (Tel Aviv, Israel), ZEB2 function was then studied in late stages of retinogenesis, and showed by combining cellular and molecular analyses that ZEB2 inhibits Müller glia cell numbers [ 86 ]. RNA-seq revealed that ZEB2 in late retinogenesis in the mouse is needed to inhibit Hes1 and also (BMP-Smad sensitive) Id genes to which ZEB2 binds, and which normally promote Müller glia cell fate and inhibit neural differentiation.…”

Section: Zeb2 In the Development Of Nervous Systems In Vertebratesmentioning

confidence: 99%

See 1 more Smart Citation

ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises

Birkhoff

Huylebroeck

Conidi

2021

Genes

Self Cite

View full text Add to dashboard Cite

After its publication in 1999 as a DNA-binding and SMAD-binding transcription factor (TF) that co-determines cell fate in amphibian embryos, ZEB2 was from 2003 studied by embryologists mainly by documenting the consequences of conditional, cell-type specific Zeb2 knockout (cKO) in mice. In between, it was further identified as causal gene causing Mowat-Wilson Syndrome (MOWS) and novel regulator of epithelial–mesenchymal transition (EMT). ZEB2’s functions and action mechanisms in mouse embryos were first addressed in its main sites of expression, with focus on those that helped to explain neurodevelopmental and neural crest defects seen in MOWS patients. By doing so, ZEB2 was identified in the forebrain as the first TF that determined timing of neuro-/gliogenesis, and thereby also the extent of different layers of the cortex, in a cell non-autonomous fashion, i.e., by its cell-intrinsic control within neurons of neuron-to-progenitor paracrine signaling. Transcriptomics-based phenotyping of Zeb2 mutant mouse cells have identified large sets of intact-ZEB2 dependent genes, and the cKO approaches also moved to post-natal brain development and diverse other systems in adult mice, including hematopoiesis and various cell types of the immune system. These new studies start to highlight the important adult roles of ZEB2 in cell–cell communication, including after challenge, e.g., in the infarcted heart and fibrotic liver. Such studies may further evolve towards those documenting the roles of ZEB2 in cell-based repair of injured tissue and organs, downstream of actions of diverse growth factors, which recapitulate developmental signaling principles in the injured sites. Evident questions are about ZEB2’s direct target genes, its various partners, and ZEB2 as a candidate modifier gene, e.g., in other (neuro)developmental disorders, but also the accurate transcriptional and epigenetic regulation of its mRNA expression sites and levels. Other questions start to address ZEB2’s function as a niche-controlling regulatory TF of also other cell types, in part by its modulation of growth factor responses (e.g., TGFβ/BMP, Wnt, Notch). Furthermore, growing numbers of mapped missense as well as protein non-coding mutations in MOWS patients are becoming available and inspire the design of new animal model and pluripotent stem cell-based systems. This review attempts to summarize in detail, albeit without discussing ZEB2’s role in cancer, hematopoiesis, and its emerging roles in the immune system, how intense ZEB2 research has arrived at this exciting intersection.

show abstract

“…Zeb2 DNA-binding around candidate direct target genes helped to explain Zeb2 loss-of-function phenotypes in ESCs and cells of early and late embryos, and in postnatal and adult mice. These genes are involved in ESC pluripotency (Nanog, Sox2), cell differentiation (Id1, Smad7), and maturation of various cell types, e.g., in embryonic cortical and adult neurogenesis (Ntf3, Sox6), as well as epithelial-to-mesenchymal transition (EMT) (Cdh1) (19)(20)(21)(22)(23)(24)(25)(26). In reverse, subtle mutagenesis of Zeb2 DNA-binding sites in demonstrated target genes has confirmed Zeb DNA-binding and its repressive activity (e.g., on mesodermal XBra (27) and epithelial Cdh1 (19)).…”

Section: Introductionmentioning

confidence: 99%

Zeb2 DNA-binding sites in neuroprogenitor cells reveal autoregulation and affirm neurodevelopmental defects, including in Mowat-Wilson Syndrome

Brouwer

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Perturbation and mechanistic studies have shown that the DNA-binding transcription factor Zeb2 controls cell fate decision, differentiation and/or maturation in multiple cell lineages in embryos and after birth. In cultured embryonic stem cells (ESCs) Zeb2 strong upregulation is necessary for their exit from primed pluripotency and entering neural and general differentiation. We engineered mouse ESCs to produce epitope-tagged Zeb2 from one of its two endogenous alleles. Using crosslinking ChIP-sequencing, we mapped for the first time 2,432 DNA-binding sites of Zeb2 in ESC-derived neuroprogenitor cells (NPCs). A new, major site maps promoter-proximal to Zeb2 itself, and its homozygous removal demonstrates that Zeb2 autoregulation is necessary to elicit proper Zeb2 effects in ESC toNPC differentiation. We then cross-referenced all Zeb2 DNA-binding sites with transcriptome data from Zeb2 perturbations in ESCs, ventral forebrain in mouse embryos, and adult neurogenesis. While the characteristics of these neurodevelopmental systems differ, we find interesting overlaps. Collectively, these new results obtained in ESC-derived NPCs significantly add to Zeb2 role as neurodevelopmental regulator as well as the causal gene in Mowat-Wilson Syndrome. Also, Zeb2 was found to map to loci mutated in other human congenital syndromes, making variant or disturbed levels of ZEB2 a candidate modifier principle in these.

show abstract

Zeb2 regulates the balance between retinal interneurons and Müller glia by inhibition of BMP–Smad signaling

Cited by 6 publications

References 78 publications

An early cell shape transition drives evolutionary expansion of the human forebrain

An early cell shape transition drives evolutionary expansion of the human forebrain

ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises

Zeb2 DNA-binding sites in neuroprogenitor cells reveal autoregulation and affirm neurodevelopmental defects, including in Mowat-Wilson Syndrome

Contact Info

Product

Resources

About