Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis

Abstract

*Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2 -/-developing eyes, a feature reminiscent of Peters' anomaly, which can be rescued by increased Pax6 gene dosage in Cited2 -/-embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1α) in Cited2 -/-lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters' anomaly and ocular hypervascularity.

p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis

“…This might be due to unidentified function(s) mediated by Shroom3 that are distinct from those involving p120-catenin. Several mouse mutants that display a similar lens stalk phenotype have disruptions in additional morphogenetic processes, such as proliferation, adhesion, differentiation and apoptosis, leaving open the possibility that Shroom3 might also function in these processes (Dimanlig et al, 2001;Ozeki et al, 2001;Medina-Martinez et al, 2005;Yoshimoto et al, 2005;Chen et al, 2008;Pontoriero et al, 2008Pontoriero et al, , 2009Kuracha et al, 2011;Cavalheiro et al, 2014).…”

HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency

“…[2][3][4][5][6] In particular, Cited2 plays an important role in fetal liver hematopoiesis, which is supported by severely impaired fetal liver HSC function and decreased expression of genes known to be essential for hematopoiesis in Cited2-deficient fetal liver HSC/progenitors. 7 Cited2 has also been implicated in tumor cell invasion and progression.…”

“…11 In our previous studies, we showed that deletion of HIF-1␣ partially rescues defects in heart and lens caused by Cited2 deficiency. 4,12 In addition, at the structural level, Freedman et al revealed that Cited2 and HIF-1␣ share a conserved "LPXL" sequence motif in their transactivation domains that interacts directly with a binding site on the CH1 region of CBP/p300. 13 HIFs are recognized as master modulators of the cellular response to hypoxic stress.…”

Cited2 Gene Controls Pluripotency and Cardiomyocyte Differentiation of Murine Embryonic Stem Cells through Oct4 Gene

“…Knockout of Cited2 is embryonic lethal, and the embryos display multiple developmental defects, including heart, lung, liver, and eyes (17)(18)(19)(21)(22)(23)(24). Mechanistically, HIF-1, TFAP2, and Nodal-Pitx2 pathways are in part responsible for heart defects in Cited2 Ϫ/Ϫ mice (17,19,20,25).…”