Expression profiling during ocular development identifies 2 Nlz genes with a critical role in optic fissure closure

Abstract

The gene networks underlying closure of the optic fissure during vertebrate eye development are poorly understood. Here, we profile global gene expression during optic fissure closure using laser capture microdissected (LCM) tissue from the margins of the fissure. From these data, we identify a unique role for the C 2H2 zinc finger proteins Nlz1 and Nlz2 in normal fissure closure. Gene knockdown of nlz1 and/or nlz2 in zebrafish leads to a failure of the optic fissure to close, a phenotype which closely resembles that seen in human uveal coloboma. We also identify misregulation of pax2 in the developing eye of morphant fish, suggesting that Nlz1 and Nlz2 act upstream of the Pax2 pathway in directing proper closure of the optic fissure.coloboma ͉ eye ͉ pax2 ͉ zinc finger protein ͉ zebrafish T he mammalian eye begins as an evagination of forebrain neuroepithelium, the optic vesicle. As the optic vesicle approaches the surface ectoderm, it invaginates upon itself, forming a double-layered optic cup attached to the brain via the optic stalk. The asymmetric nature of this invagination leads to the formation of a gap along the ventral optic cup and optic stalk (the optic fissure) that remains open for hours to days, depending on the species. To form a spherical globe the margins of the optic fissure must meet and fuse ventrally during the 5th-7th

Retinoic acid receptor signaling regulates choroid fissure closure through independent mechanisms in the ventral optic cup and periocular mesenchyme

“…Thus, foxC1a and pitx2 morphants (in this study) or nlz1 morphants (18) show subtle colobomata, without overt effects on earlier eye morphogenesis or on the expression of VR/OS genes. Fewer POM cells enter the choroid fissure after inhibition of RAR function, and we speculate that POM cells invading the fissure facilitate the fusion of the ventral lips of the optic cup.…”

“…6A). Abrogation of Nlz1 is also reported to cause coloboma (18). Despite defective choroid fissure morphogenesis, there were no evident effects on the expression of the VR/OS genes vax1, net1a, cyb5a, and itgA5 in foxC1a, nlz1, or pitx2 morphants (Fig.…”

“…RAR-dependent regulation of their expression is centered around a developmental window (between 18s and 23 hpf) coinciding with the invagination of the optic cup. Abrogation of Vax1 or Nlz2 function causes coloboma (11,18). Dact1 functions in morphogenetic processes by regulating the planar cell polarity pathway (22).…”

“…Roles in choroid fissure closure are well documented for genes expressed in VR/OS cells (11,17,18), but the requirements for POM genes are less well studied. Consequently, we abrogated the activity of selected RAR-regulated POM genes with morpholino antisense oligonucleotides (MOs) and assessed ventral eye morphogenesis and the expression of VR/OS and other POM genes.…”

Zeppo1 is a novel metastasis promoter that repressesE-cadherinexpression and regulates p120-catenin isoform expression and localization

“…Zpo1 is a member of the NET (Noc/Nlz, Elbow, and Tlp-1) family of proteins (Nakamura et al 2004) that function in embryonic development in zebrafish (Hoyle et al 2004;Brown et al 2009), Drosophila (Dorfman et al 2002), and Caenorhabditis elegans (Zhao et al 2002). We show here that Zpo1 functions as a transcriptional repressor.…”