The Zic2 gene directs the formation and function of node cilia to control cardiac situs

Abstract

Summary: The first molecular herald of organ asymmetry during murine embryogenesis is found at the periphery of the node in early-somite stage embryos. Asymmetric gene expression and calcium accumulation at the node occurs in response to a left-ward flow of extracellular fluid across the node, generated by motile cilia within the pit of the node and likely sensed by immotile cilia in the periphery of the node. The ciliation of node cells is controlled by a cascade of node-restricted transcription factor activity during mid-late gastrulation. Mutation of the murine Zic2 transcription factor is associated with random cardiac situs and a loss of asymmetric gene expression at the early-somite node and in the lateral plate. Zic2 is not expressed in these regions but is transiently expressed in the mid-late gastrula node at the time of ciliogenesis. The cilia of the node are overtly abnormal in Zic2 mutant embryos being dysmorphic and short relative to wild-type littermates. The expression of the Noto, Rfx3, and Foxj1 transcription factors known to regulate ciliogenesis is greatly depleted in the midgastrula node of mutants, as is the expression of the Pkd1l1 gene required for cilia function. Zic2 appears to be a component of the gene regulatory network that drives ciliation of node cells during gastrulation. genesis 52:626-635,

Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis

“…This hypothesis is supported by the partial rescue of coloboma by Hh inhibition in MZ-zic2 mutants. Notably, mouse zic2 promotes formation of the embryonic organizer during gastrulation (Barratt et al, 2014; Houtmeyers et al, 2016; Warr et al, 2008). …”

Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF-β, hedgehog, and FGF signaling

“…HPE is best understood as a conserved sequence of developmental steps that begin in the early gastrulating embryo (Arnold & Robertson, 2009). Driver genes are inextricably linked to this developmental sequence, beginning with TGF-signals around the node (Barratt, Glanville-Jones, & Arkell, 2014;Beddington & Robertson, 1999;Houtmeyers et al, 2016;Powers et al, 2010;Robertson, 2014;Warr et al, 2008), the establishment of the primitive streak and its midline progenitors (Herion, Salbaum, & Kappen, 2014), the precise positioning of the prechordal plate beneath the midline neuro-ectoderm (England, Blanchard, Mahadevan, & Adams, 2006), the activation of midline hedgehog signals (Geng et al, 2008;Jeong et al, 2008;Ohkubo, Chiang, & Rubenstein, 2002;Okada, Okumura, Motoyama, & Ogawa, 2008), and/or cooperating with them in the forebrain (Carlin et al, 2012;Gestri et al, 2005;Geng, Acosta, Lagutin, Gil, & Oliver, 2016;Lavado, Lagutin, & Oliver, 2008;Lee et al, 2017;Storm et al, 2006).…”

Genome-wide CRISPR screen identifies ZIC2 as an essential gene that controls the cell fate of early mesodermal precursors to human heart progenitors

“…Studies in mutant mice showed that HPE is produced by a transient defect in the development of prechordal plate, a structure required for forebrain midline morphogenesis, validating the function of Zic2 during organizer formation . The Zic2 null mice have cardiac situs problems, indicating a L‐R axis patterning defect . By examining the embryos at later stages, more cardiovascular malformations have been found, such as abnormal ventricular topology, great artery transposition, double outlet right ventricle, ventricular septal defect, and rightward looped aortic arch .…”