Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen

Abstract

Retinoic acid (RA) is essential for both embryonic and adult growth, activating gene transcription via specific nuclear receptors. It is generated, via a retinaldehyde intermediate, from retinol (vitamin A). RA levels require precise regulation by controlled synthesis and catabolism, and when RA concentrations deviate from normal, in either direction, abnormal growth and development occurs. This review describes: (i) how the pattern of RA metabolic enzymes controls the actions of RA; and (ii) the type of abnormalities that result when this pattern breaks down. Examples are given of RA control of the anterior/posterior axis of the hindbrain, the dorsal/ventral axis of the spinal cord, as well as certain sex-specific segments of the spinal cord, using varied animal models including mouse, quail and mosquitofish. These functions are highly sensitive to abnormal changes in RA concentration. In rodents, the control of neural patterning and differentiation are disrupted when RA concentrations are lowered, whereas inappropriately high concentrations of RA result in abnormal development of cerebellum and hindbrain nuclei. The latter parallels the malformations seen in the human embryo exposed to RA due to treatment of the mother with the acne drug Accutane (13-cis RA) and, in cases where the child survives beyond birth, a particular set of behavioural anomalies can be described. Even the adult brain may be susceptible to an imbalance of RA, particularly the hippocampus. This report shows how the properties of RA as a neural induction agent and organizer of segmentation can explain the consequences of RA depletion and overexpression.

A Disorder to Order Transition Accompanies Catalysis in Retinaldehyde Dehydrogenase Type II

“…The mutant enzyme RalDH2:L458F/N459G has 66% of the activity for acetaldehyde of the wild-type enzyme over a concentration range of 0.250 -32 mM substrate. However, the data for the mutant enzyme exhibit negative cooperativity; the data fit best to a double rectangular hyperbola based of the fact that the average least squares of the residuals were the lowest for Equation 1. It is interesting to note that V max (1) for the mutant enzyme is equivalent to the V max of the wild-type enzyme.…”

“…The consequences of deregulation of this process are tragic; the teratogenic effects of retinoic acid analogs used to treat cystic acne are thought to be a result of aberrant retinoic acid concentrations during morphogenesis (1). In their studies of the developing spinal cord, McCaffery and Drager (2) observed retinal dehydrogenase activity with the same spatiotemporal distribution as that of retinoic acid and subsequently identified the enzyme retinaldehyde dehydrogenase type II (RalDH2) 1 in their examination of the effect of retinoic acid signaling in the formation of the neural axis (3). Similar studies suggested a role for RalDH2 in the developing mammalian heart (4).…”

Fate of retinoic acid–activated embryonic cell lineages

“…The pattern of reporter excision observed in RARE-Cre;R26R embryos may reflect these two phases of RA activity, considering that during the first phase the pulse of RA may be too short to activate the RARE-Cre transgene and generate sufficient amounts of Cre, except in a few pre-r3/r4 cells. However, the graded, increasing distribution of X-galþ cells from r3 toward r6 may better fit with the ''classical'' view of a gradient diffusion of RA from the posterior hindbrain mesoderm (discussed in Gavalas, 2002;Maden, 2002;McCaffery et al, 2003;White and Schilling, 2008) and/or with the model of a temporally increasing source of RA during the formation of progressively more posterior rhombomeres (Maves and Kimmel, 2005). Eventually, the induction of all three CYP26 enzymes in distinct rhombomeric territories may lead to differential RA responsiveness along the hindbrain anteroposterior axis (Hernandez et al, 2007;White and Schilling, 2008).…”

“…Many studies have dealt with the involvement of RA signaling in patterning of the segmented embryonic hindbrain or rhombencephalon (for reviews, Gavalas, 2002;Maden, 2002;McCaffery et al, 2003;White and Schilling, 2008). Conditions of RA excess through maternal administration (Marshall et al, 1992;Simeone et al, 1995, and references therein) or Cyp26 knock-down Sakai et al, 2001;Emoto et al, 2005;Hernandez et al, 2007), and of RA deficiency through mutation of Rdh10 or Raldh2 (Niederreither et al, 2000;Sandell et al, 2007), have severe effects on hindbrain development and can lead to changes in rhombomeric molecular identities.…”

Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

“…Retinoic acids (RAs), which appear to be involved in vertebrate morphogenesis, are natural and synthetic derivatives of vitamin A (Maden, 2001;McCaffery et al, 2003), and exert their biological functions through nuclear receptors including RA receptors (RARs) and retinoid X receptors (RXRs) (Lippman and Lotan, 2000). In response to RA binding, RAR/RXR heterodimers regulate the transcription of a number of target genes by binding to the specific DNA response elements (Balmer and Blomhoff, 2002).…”