Distinct functions for Aldh1 and Raldh2 in the control of ligand production for embryonic retinoid signaling pathways

Abstract

During vertebrate embryogenesis retinoic acid (RA) synthesis must be spatiotemporally regulated in order to appropriately stimulate various retinoid signaling pathways. Various forms of mammalian aldehyde dehydrogenase (ALDH) have been shown to oxidize the vitamin A precursor retinal to RA in vitro. Here we show that injection of Xenopus embryos with mRNAs for either mouse Aldh1 or mouse Raldh2 stimulates RA synthesis at low and high levels, respectively, while injection of human ALDH3 mRNA is unable to stimulate any detectable level of RA synthesis. This provides evidence that some members of the ALDH gene family can indeed perform RA synthesis in vivo. Whole-mount immunohistochemical analyses of mouse embryos indicate that ALDH1 and RALDH2 proteins are localized in distinct tissues. RALDH2 is detected at E7.5-E10.5 primarily in trunk tissue (paraxial mesoderm, somites, pericardium, midgut, mesonephros) plus transiently from E8.5-E9.5 in the ventral optic vesicle and surrounding frontonasal region. ALDH1 is first detected at E9.0-E10. 5 primarily in cranial tissues (ventral mesencephalon, dorsal retina, thymic primordia, otic vesicles) and in the mesonephros. As previous findings indicate that embryonic RA is more abundant in trunk rather than cranial tissues, our findings suggest that Raldh2 and Aldh1 control distinct retinoid signaling pathways by stimulating high and low RA biosynthetic activities, respectively, in various trunk and cranial tissues.

Quantitative axial profiles of retinoic acid in the embryonic mouse spinal cord: 9‐Cis retinoic acid only detected after all‐trans‐retinoic acid levels are super‐elevated experimentally

“…The immunostaining confirms the tissue distribution of RALDH2 demonstrated previously in both mouse and chicken embryos. RALDH2 is expressed in the roof plate, in motoneurons of the lateral motor column (restricted to brachial and lumbar regions), and in the surrounding meninges and adjacent mesenchyme, as well as other sites further removed from the spinal cord (Zhao et al, 1996;Niederreither et al, 1997;Sockanathan and Jessell, 1998;Berggren et al, 1999;Haselbeck et al, 1999). These earlier studies did not assess axial differences in RALDH2 expression in tissues outside the neural tube.…”

Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development

“…It functions downstream of alcohol dehydrogenases, which catalyze the reversible oxidation of retinol (vitamin A) to retinaldehyde (Molotkov et al, 2002). Expression of Raldh2 in mouse embryos is first observed posteriorly in paraxial and lateral plate mesoderm during the late primitive streak stage (Niederreither et al, 1997;Haselbeck et al, 1999). RA signaling activity in mouse embryos is also first observed posteriorly at the late primitive streak stage (Rossant et al, 1991;Ang et al, 1996).…”

Methods for detecting and identifying retinoids in tissue

“…Instead, the RA molecule is inactivated in several locations by different enzymes. These enzyme types have been demonstrated to play an essential role in retinoid signaling and show discrete domains of expression during embryonic development (Ang and Duester, 1999;Haselbeck et al, 1999;Schneider et al, 2001). …”