PIAS-like protein Zimp7 is required for the restriction of the zebrafish organizer and mesoderm development

Abstract

The Zmiz2 (Zimp7) protein and its homolog Zmiz1 (Zimp10) were initially identified in humans as androgen receptor co-activators. Sequence analysis revealed the presence of an SP-RING/Miz domain, which is highly conserved in members of the PIAS family and confers SUMO-conjugating activity. Zimp7 has been shown to interact with components of the Wnt/β-Catenin signaling pathway and with Brg1 and BAF57, components of the ATP-dependent mammalian SWI/SNF-like BAF chromatin-remodeling complexes. In this work, we analyze the role of zygotic Zimp7 in zebrafish development. We describe evidence indicating that Zimp7 is required for mesoderm development and dorsoventral patterning. Morpholino-mediated reduction of zygotic Zimp7 produced axial mesodermal defects that were preceded by up-regulation of organizer genes such as bozozok, goosecoid and floating head at the onset of gastrulation and by down-regulation of the ventral markers vox, vent and eve1 indicating loss of the ventrolateral mesoderm. Consistently, embryos overexpressing zimp7 RNA exhibited midline defects such as loss of forebrain and cyclopia accompanied by transcriptional changes directly opposite of those found in the morphants. In addition, the patterning of ventralized embryos produced by the overexpression of vox and vent was restored by a reduction of Zimp7 activity. Altogether, our findings indicate that Zimp7 is involved in transcriptional regulation of factors that are essential for patterning in the dorsoventral axis.

A Deficiency in SUMOylation Activity Disrupts Multiple Pathways Leading to Neural Tube and Heart Defects inXenopusEmbryos

“…Gam1 knockdown of SUMOylation activity reproducibly generated distinct developmental phenotypes, several of which have been previously linked to disruptions of this post-translational modification, including neural tube closure [26], cleft lip/palate [27], heart defects [28--30], axial mesodermal defects that lead to midline phenotypes such as cyclopia [31], and disruption of hematopoiesis [32]. In good accord with the Gam1 phenotypes, a morpholino antisense oligonucleotide directed against Xenopus SUMO1 caused shortened and bent A--P axes, incomplete closure of the neural tube, microcephaly, and inhibition of activin--induced elongation of animal caps [15].…”

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

“…63,64 Similar to well-established PLT-and MPV-associated transcriptional regulator JMJD1C, ZMIZ2 directly interacts with AR to modulate AR-mediated transcription and influences mesodermal development, and thus genetic variation in ZMIZ2 could potentially contribute to hormonally mediate differences in PLT across genders. [65][66][67] Also associated with increased PLT and decreased RBC indices was rs55707100 in MAP1A. 18 Though typically examined in a neurological context, MAP1A is involved in microtubule assembly, a process important in blood cell development and function.…”

“…Loos, 13 Albert Vernon Smith, 59,60 Tamara B. Harris, 61 Lenore J. Launer, 61 Vilmundur Gudnason, 59,60 Digna R. Velez Edwards, 62 Eric S. Torstenson, 19 Yongmei Liu, 63 Russell P. Tracy, 64 Jerome I. Rotter, 65,66 Stephen S. Rich, 22 Heather M. Highland, 67,68 Eric Boerwinkle, 18,69 Jin Li, 70 Ethan Lange, 21,71 James G. Wilson, 72 Evelin Mihailov, 73 Reedik Mägi, 73 Joel Hirschhorn, 7,74 Andres Metspalu, 73 Tõnu Esko, 7,73 Caterina Vacchi-Suzzi, 75 Mike A. Nalls, 76 Alan B. Zonderman, 12 Michele K. Evans, 12 Gunnar Engström, 77,78 Marju Orho-Melander, 77 We thank all participants and study coordinating centers. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the NIH, or the U.S. Department of Health and Human Services.…”

The chromatin factor Gon4l regulates embryonic axis extension by promoting mediolateral cell polarity and notochord boundary formation through negative regulation of cell adhesion

“…12 13 Mediolateral polarity and intercalation of axial mesoderm cells are reduced in MZudu-/-gastrulae 14 In vertebrate gastrulae, C&E is achieved chiefly through ML intercalation of polarized cells that elongate and 15 align their cell bodies with the ML embryonic axis 5,7,9,11 . To determine whether cell polarity defects underlie 16 reduced axis extension in MZudu-/-gastrulae, we measured cell orientation (the angle of a cell's long axis with 17 respect to the embryo's ML axis; Fig.3b,e) and cell body elongation (length-to-width or aspect ratio (AR); 18 Fig.3c,f) in confocal time-lapse series of MZudu-/-and WT gastrulae expressing membrane Cherry fluorescent 19 protein (mCherry). Given the irregular notochord boundaries observed in MZudu-/-gastrulae ( Fig.2d-e), we 20 examined the time course of cell polarization according to a cell's position with respect to the boundary: i.e.…”

“…Epigenetic modifiers like Histone acetyl 6 transferases (HATs), deacetylases (HDACs), and methyltransferases associate within protein complexes 7 containing chromatin factors that are thought to regulate their binding at specific genomic regions in context-8 specific ways 16 . The identities, functions, and specificity of chromatin factors with roles during embryogenesis 9 are only now being elucidated, and often have described roles in cell fate specification and embryonic 10 patterning [17][18][19] . The contribution of epigenetic regulation to gastrulation cell movements, however, is particularly 11 poorly understood.…”