Retinoic acid regulates the expression of dorsoventral topographic guidance molecules in the chick retina

Abstract

Asymmetric expression of several genes in the early eye anlagen is required for the dorsoventral (DV) and anteroposterior (AP) patterning of the retina. Some of these early patterning genes play a role in determining the graded expression of molecules that are needed to form the retinotectal map. The polarized expression of retinoic acid synthesizing and degrading enzymes along the DV axis in the retina leads to several zones of varied retinoic acid (RA)activity. This is suggestive of RA playing a role in DV patterning of the retina. A dominant-negative form of the retinoic acid receptor α(DNhRARα) was expressed in the chick retina to block RA activity. RA signaling was found to play a role in regulating the expression of EphB2,EphB3 and ephrin B2, three molecules whose graded expression in the retina along the DV axis is important for establishing the correct retinotectal map. Blocking RA signaling by misexpression of a RA degrading enzyme, Cyp26A1 recapitulated some but not all the effects of DNhRARα. It also was found that Vax, a ventrally expressed transcription factor that regulates the expression of the EphB and ephrin B molecules, functions upstream of, or in parallel to, RA. Expression of DNhRARα led to increased levels of RA-synthesizing enzymes and loss of RA-degrading enzymes. Activation of such compensatory mechanisms when RA activity is blocked suggests that RA homeostasis is very strictly regulated in the retina.

Diverse Functions of Retinoic Acid in Brain Vascular Development

“…Modulation of WNT signaling by RA signaling likely occurs at the level of RAR␣, which we show here is the main RAR expressed in fetal brain ECs. RARs can interact with components of the WNT transcriptional complex, which includes ␤-catenin, TCF members, and Lef1, and through these interactions modulate WNTmediated transcription (Easwaran et al, 1999;Shah et al, 2003). Future work looking at the direct interactions between proteins in these two pathways will provide insight into how brain ECs integrate RA and WNT signaling appropriately during brain vascular development.…”

“…To do this, cells were cotransfected with the same dominant-negative RAR␣ construct (dnRAR␣403) used to construct the dnRAR403-flox allele used in our in vivo experiments (Damm et al, 1993;Sen et al, 2005). Expression of this truncated construct interferes with endogenous RA signaling because the transcriptional regulatory domain of the receptor is deleted (Damm et al, 1993;Sen et al, 2005;Rajaii et al, 2008). Expression of the dnRAR␣403 construct in cells without treatment of WNT3a or RA had no effect on TOP-Flash reporter activity (Fig.…”

A typology of photoreceptor gene expression patterns in the mouse

“…Exactly the same number of genes was found to be enriched in the dorsal retina, using the same criteria (SI Table 10). Five of the 10 most highly enriched ''dorsal'' genes were genes previously shown to be enriched in the dorsal retina: Tbx5, Ephrin B2 (Efnb2), COUP-TFII (Nr2f2), Raldh1 (Aldh1a1), and Cyb1b1 (13)(14)(15)(16)(17)(18). In addition, the two dorsal Ͼ ventral cone genes discussed above, Opn1mw (M-opsin), Smug1, and one additional cone gene, Arr3, were also found to be among the top 21 most dorsally enriched genes.…”

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

“…Finally, exogenous retinoic acid can improve aspects of alveolar formation in animal models of lung disease (Shifren and Mecham, 2006;Pierce et al, 2007;Stinchcombe and Maden, 2008) through both improved matrix production and pro-angiogenic effects. Interestingly, ephrinB2 expression is increased by retinoic acid and endogenous retinoids in other systems (Merrill et al, 2004;Sen et al, 2005) and could be modulate the effects of this system. It will be of interest to relate the loss-of-function in the ephrinB2 line to known signaling cascades affecting lung development.…”