Different E-box binding transcription factors, similar neuro-developmental defects: ZEB2 (Mowat-Wilson syndrome) and TCF4 (Pitt-Hopkins syndrome)

Abstract

ZEB2 and TCF4 are transcription factors (TFs) whose locations in embryos overlap in many sites and developmental phases, including in the forebrain and its cortical neurons. De novo mutations cause the phenotypically overlapping, haploinsufficient Mowat-Wilson (MOWS, in the ZEB2 gene) and Pitt-Hopkins (PTHS, in TCF4) syndromes, which currently cannot be cured. Mutant alleles have been mapped and defects documented (also in brain function) in MOWS and PTHS patients. Appropriately designed mouse models and cells derived from these, as well as cellular models including cultured pluripotent cells, enable investigating the genetic and molecular mechanisms underlying the developmental deficiencies that manifest after birth in the nervous systems and their multiple cell types, as well as those of organs other than the brain, in MOWS and PTHS. Biochemical analyses of cell type-specific transcriptomic changes in these perturbation models as compared to control cells, the identification of the intact-factor dependent and direct target genes, and of partner proteins including chromatin modulators, are revealing complex and multiple modes of action that eventually will explain target gene selectivity for these TFs. Both TFs have also been found to operate in acute and chronic diseases and cell-based repair processes after tissue or organ injury. In addition, the defective function also arises from their aberrant gene expression, which will require a deeper investigation of how the transcription of these TF genes is regulated. Furthermore, these two factors genetically and biochemically interact. This review combines the essentials and recent progress for both TFs for the first time, with a focus on MOWS and PTHS.

Zeb2 DNA-Binding Sites in Neuroprogenitor Cells Reveal Autoregulation and Affirm Neurodevelopmental Defects, Including in Mowat-Wilson Syndrome

“…Here, Zeb2 generates anti-BMP(-Smad)/anti-Wnt(-β-catenin) activities, which is crucial for CNS myelinogenesis by differentiation of OPCs. The regulatory action of Zeb2 on the Tcf4 target gene, as found in mouse cells by our ChIP-seq, may underpin phenotypic similarities between MOWS and Pitt-Hopkins syndrome patients (PTHS, OMIM #610954; for a recent discussion, see [ 57 ]) the latter caused by mutations in TCF4 [ 58 ], making us speculate that TCF4 may be deregulated in neural cells in MOWS.…”

“…Interestingly, some of these candidate genes for priority inclusion in future MOWS cell-based studies also emanated from independently overlooking all mapped GWBS for Zeb2 from this study (in Table S1 ) with an eye for anticipated MOWS cell biological defects, focusing mainly on neural and glial cells. These genes include Bcl11 (developmental intellectual disorders, agenesis of corpus callosum), Caln1 , Efna5 , Galnt5/6 , Gng4/7 , Isl1 (a TF that regulates expression of Slit and Robo genes), Klf2/7/14 , Nalcn , Pax6 , Pcdh9/20 , Pipox , Pou3f/4f members (one also known as Brn3a ), Ror2 , Sema3 , Slc14a2 , Sox1 , Tcf4 (see [ 57 ] for a detailed discussion), Tubb3/6 , and of course Zeb2 . From Table S1 , we would also prioritize genes for adhesion G-coupled receptors (e.g., Adgre5 , Adgrl2 ), adherens junctions ( Ajap1 , Frmd4a , Jam3 ), several Cdh genes, genes involved in Wnt ( Axin2 , Kremen1 ) or BMP signaling ( Rgmb , Ror2 ), sulfotransferase-encoding genes ( Chst2/7 , Hs3st3a1 , Ndst1 ), Camkk1 (for MOWS patients have CAMK deficiency), chemokine receptor genes ( Ccr1/7 ), Ddx10/18 , Efhb , Fgf14 , Lrrc4c (encoding a binding partner of long-range guidance cue Netrin G1), Nrn1 (encoding a neuritin, involved in neuronal plasticity), Pitx2 , Plk2 (encoding a kinase that links to epilepsy), Prex1 , Prox1 , Robo2 , Six2 , Snai3 , Sox5 , Tenm3 (for proper connectivity in the nervous system), and Tox3 (chromatin bending).…”

“…It is also intriguing that Zeb2 is recruited to and controlling Tcf4 at D8, and that Tcf4 is deregulated upon Zeb2-KD (using esiRNA [ 37 ], and here shRNA). Mutations in TCF4 cause PTHS, a rare neurodevelopmental disorder with some defects overlapping with MOWS (for an extensive discussion, see [ 57 ]). The binding of Zeb2 to Tcf4 opens new attractive roads to further investigate the crosstalk between these two TFs and their role in regulating crucial aspects of neurodevelopment.…”