Retinoic acid signaling in the brain marks formation of optic projections, maturation of the dorsal telencephalon, and function of limbic sites

Abstract

As retinoic acid (RA) is known to regulate the expression of many neuronal proteins, it is likely to influence overall development and function of the brain; few particulars, however, are available about its role in neurobiological contexts due mainly to problems in RA detection. To ask whether the function of RA in the rostral brain is concentrated in particular neurobiological systems, we compared sites of RA synthesis and actions, as detected by RA signaling in reporter mice, for embryonic and adult ages. We found that most sites of RA actions in the forebrain do not colocalize with RA synthesis, consistent with a dominant RA supply by diffusion and the circulation. The changing RA patterns distinguish preferentially two complex functional schemes. (1) Within the visual system when the first optic axons grow toward their targets, RA signaling delineates the topographical adjustment of the retinal map, which is encoded in the coordinates of the visual world, to central visual maps, which are formed in the segmental brain coordinates. (2) The second scheme begins early in forebrain morphogenesis as a distinction of the dorsal telencephalon. With progressing development, and in the adult, the RA patterns then focus on widely distributed structures, most of which belong to the limbic system. These are sites in which emotional perception is combined with higher cognitive processes and in which normal function requires ongoing remodeling of synaptic connections, indicating that the developmental role of RA in promotion of neuronal differentiation programs continues in the adult brain for highly flexible neural circuits. J. Comp. Neurol. 470:297-316, 2004.

The neurobiology of retinoic acid in affective disorders

“…Several such transgenic lines exist and use either 1) a transgene consisting of a RARE driving a lacZ reporter gene (Colbert et al 1993;Rossant et al 1991) to report RA induced gene transcription or 2) a fusion of the Gal-4 DNA-binding domain linked with the ligand-binding domain of RAR alpha -when these mice are crossed with reporter mice with lacZ controlled by an upstream activating sequence then these report RA binding to the RA receptor . In the embryo, these reporter mice show RA signaling in a variety of regions in the CNS (Colbert et al 1993;Luo et al 2004b;Mata De Urquiza et al 1999;Zhang et al 2003); however, as the CNS matures, RA signaling is restricted to progressively limited regions (Thompson Haskell et al 2002). This deactivation of the RA signaling system is not due to restricted amounts of RA however, since injections of RA into the reporter mouse do not activate the reporter in regions in which it is not already expressed (Luo et al 2004b), thus this loss of responsiveness is presumably at a genomic level.…”

“…In the embryo, these reporter mice show RA signaling in a variety of regions in the CNS (Colbert et al 1993;Luo et al 2004b;Mata De Urquiza et al 1999;Zhang et al 2003); however, as the CNS matures, RA signaling is restricted to progressively limited regions (Thompson Haskell et al 2002). This deactivation of the RA signaling system is not due to restricted amounts of RA however, since injections of RA into the reporter mouse do not activate the reporter in regions in which it is not already expressed (Luo et al 2004b), thus this loss of responsiveness is presumably at a genomic level. Regions of the brain that exhibit RA signaling as determined using RA reporter mice include the limbic system, in particular the hippocampus (section 2.4) (Krezel et al 1999;Luo et al 2004b;Misner et al 2001;Sakai et al 2004;Zetterstrom et al 1999) as well as the medial prefrontal cortex including prefrontal and cingulate cortex and retrosplenial area together with subregions of the thalamus and hypothalamus (Luo et al 2004b).…”

“…This deactivation of the RA signaling system is not due to restricted amounts of RA however, since injections of RA into the reporter mouse do not activate the reporter in regions in which it is not already expressed (Luo et al 2004b), thus this loss of responsiveness is presumably at a genomic level. Regions of the brain that exhibit RA signaling as determined using RA reporter mice include the limbic system, in particular the hippocampus (section 2.4) (Krezel et al 1999;Luo et al 2004b;Misner et al 2001;Sakai et al 2004;Zetterstrom et al 1999) as well as the medial prefrontal cortex including prefrontal and cingulate cortex and retrosplenial area together with subregions of the thalamus and hypothalamus (Luo et al 2004b). One suggested common feature of several of the regions of RA signaling is that these are areas of high neuronal plasticity (McCaffery et al 2006;Thompson Haskell et al 2002).…”

“…It is possible, for instance, that epigenetic mechanisms may exist to silence the RARE-reporter transgene, while allowing RAREs associated with other genes to function. An example in the embryo of a region where RA signaling occurs, but no reporter response is evident, is the ganglionic eminence, which is responsive to RA (Toresson et al 1999a;Waclaw et al 2004) and is a region of RA synthesis via the RALDH3 enzyme but shows little expression of the RA reporter (Luo et al 2004b). Thus, it is possible that RA signaling may prove to be more extensive in the brain.…”

Calmin expression in embryos and the adult brain, and its regulation by all‐trans retinoic acid

“…Impairment of synaptic plasticity and a deficiency in spatial learning is also observed in RARb knockout mice (Chiang et al, 1998). Furthermore, retinoid activity is present in the adult hippocampus as evidenced by several in vivo RA reporter systems (Misner et al, 2001;Luo et al, 2004). Whether CLMN plays a role in any of these events remains to be determined.…”