Retinoids are produced by glia in the lateral ganglionic eminence and regulate striatal neuron differentiation

Abstract

In order to identify molecular mechanisms involved in striatal development, we employed a subtraction cloning strategy to enrich for genes expressed in the lateral versus the medial ganglionic eminence. Using this approach, the homeobox gene Meis2 was found highly expressed in the lateral ganglionic eminence and developing striatum. Since Meis2 has recently been shown to be upregulated by retinoic acid in P19 EC cells (Oulad-Abdelghani, M., Chazaud, C., Bouillet, P., Sapin, V., Chambon, P. and Dolle, P. (1997) Dev. Dyn. 210, 173–183), we examined a potential role for retinoids in striatal development. Our results demonstrate that the lateral ganglionic eminence, unlike its medial counterpart or the adjacent cerebral cortex, is a localized source of retinoids. Interestingly, glia (likely radial glia) in the lateral ganglionic eminence appear to be a major source of retinoids. Thus, as lateral ganglionic eminence cells migrate along radial glial fibers into the developing striatum, retinoids from these glial cells could exert an effect on striatal neuron differentiation. Indeed, the treatment of lateral ganglionic eminence cells with retinoic acid or agonists for the retinoic acid receptors or retinoid X receptors, specifically enhances their striatal neuron characteristics. These findings, therefore, strongly support the notion that local retinoid signalling within the lateral ganglionic eminence regulates striatal neuron differentiation.

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

“…Out of the three Meis genes, only Meis1 and Mei2 are expressed in the developing telencephalon ( Figure 1B ). Meis2 in particular is an important player for striatal progenitors and neuron differentiation, as well as postnatal neuronal differentiation in the olfactory bulb ( Toresson et al, 1999 ; Agoston et al, 2014 ).…”

“…Myeloid ectopic viral integration site 2 is expressed in the VZ of the entire telencephalon from E10.5, and is enriched in the LGE compared to the MGE from E12.5 to E18.5 ( Figure 1B ). From E14.5, MEIS2 is also expressed in the ventral thalamus and the anterior hypothalamus ( Cecconi et al, 1997 ; Toresson et al, 1999 , 2000 ). Additionally, the expression pattern of MEIS2 is similar in the human fetal forebrain, where MEIS2 is expressed in the proliferative zones ( Larsen et al, 2010a ).…”

“…Additionally, the expression pattern of MEIS2 is similar in the human fetal forebrain, where MEIS2 is expressed in the proliferative zones ( Larsen et al, 2010a ). In the telencephalon, MEIS2 was initially considered as an LGE-specific marker due to its predominant expression in the LGE; however, MEIS2 is also widely expressed in the CGE progenitors ( Toresson et al, 1999 ; Frazer et al, 2017 ). Postnatally, interneurons born and derived from the olfactory bulb express MEIS2, as it plays a crucial role, along with other transcription factors, in neuronal differentiation and specification in early postnatal stages ( Allen et al, 2007 ; Agoston et al, 2014 ).…”

“…The LGE can be further separated in the ventral LGE (vLGE), where striatal projection neurons originate, and the dorsal LGE (dLGE) that gives rise to intercalated cells of the amygdala and neurons in the olfactory bulb along with the lateral LGE wall ( Yun et al, 2001 ; Stenman et al, 2003 ; Waclaw et al, 2010 ). The LGE is a local source of retinoic acid, a morphogen that regulates cortical patterning and regionalization (see Shibata et al, 2021 ; Ziffra et al, 2021 for more details) ( Toresson et al, 1999 ; Molotkova et al, 2007 ; Shibata et al, 2021 ; Ziffra et al, 2021 ).…”

“…The main population of striatal projection neurons comprises the GABAergic medium spiny neurons (MSNs) which arise from progenitors in the LGE, and account for ∼ 80% of the striatal neuron population in primates and rodents ( Graveland and DiFiglia, 1985 ). Some key marker genes for MSN differentiation include Foxp1/2 , Ascl1 , Ebf1 , and Meis2 ( Garel et al, 1999 ; Toresson et al, 1999 ; Carri et al, 2013 ). The differentiation of MSNs is dependent on the temporal expression of a set of transcription factors, particularly the repressive function of Dlx1/2 on Ascl1 at specific timepoints, to promote differentiation and migration of striatal neurons ( Anderson et al, 1997b ; Yun et al, 2002 ).…”