Modular patterning of structure and function of the striatum by retinoid receptor signaling.

Retinoid signaling plays a crucial role in patterning rhombomeres in the hindbrain and motor neurons in the spinal cord during development. A fundamentally interesting question is whether retinoids can pattern functional organization in the forebrain that generates a high order of cognitive behavior. The striatum contains a compartmental structure of striosome (or "patch") and intervening matrix. How this highly complex mosaic design is patterned by the genetic programs during development remains elusive. We report a developmental mechanism by which retinoid receptor signaling controls compartmental formation in the striatum. We analyzed RARbeta(-/-) mutant mice and found a selective loss of striosomal compartmentalization in the rostral mutant striatum. The loss of RARbeta signaling in the mutant mice resulted in reduction of cyclin E2, a cell cycle protein regulating transition from G(1) to S phase, and also reduction of the proneural gene Mash1, which led to defective neurogenesis of late-born striosomal cells. Importantly, during striatal neurogenesis, endogenous levels of retinoic acid were spatiotemporally regulated such that transduction of high levels of retinoic acid through RARbeta selectively expanded the population of late-born striosomal progenitors, which evolved into a highly elaborate compartment in the rostral striatum. RARbeta(-/-) mutant mice, which lacked such enlarged compartment, displayed complex alternations of dopamine agonist-induced stereotypic motor behavior, including exaggeration of head bobbing movement and reduction of rearing activity. RARbeta signaling thus plays a crucial role in setting up striatal compartments that may engage in neural circuits of psychomotor control.

Differential expression of RARbeta isoforms in the mouse striatum during development: a gradient of RARbeta2 expression along the rostrocaudal axis.

The retinoic acid receptor RARbeta is highly expressed in the striatum of the ventral telencephalon. We studied the expression pattern of different RARbeta isoforms in the developing mouse striatum by in situ hybridization. We found a differential ontogeny of RARbeta2 and RARbeta1/3 in embryonic day (E) 13.5 lateral ganglionic eminence (striatal primordium). RARbeta2 mRNA was detected primarily in the rostral and ventromedial domains, whereas RARbeta1/3 mRNAs were enriched in the caudal and dorsolateral domains. Notably, by E16.5, a prominent decreasing gradient of RARbeta2 mRNA was present in the developing striatum along the rostrocaudal axis, i.e., RARbeta2 was expressed at higher levels in the rostral than the caudal striatum. No such gradient was found for RARbeta1/3 and RARbeta3 mRNAs. The rostrocaudal RARbeta2 gradient gradually disappeared postnatally and was absent in the adult striatum. The differential expression pattern of RARbeta isoforms in the developing striatum may provide an anatomical basis for differential gene regulation by RARbeta signaling.

Retinoid signaling competence and RARbeta-mediated gene regulation in the developing mammalian telencephalon.

To study retinoid signaling in the developing telencephalon, we transfected a retinoid reporter gene into different regions of developing telencephalon. We found that the ventral telencephalon was more competent to retinoid signaling than the dorsal telencephalon. Moreover, among all retinoic acid receptors (RARs) and retinoid X receptors (RXRs), RARbeta was strongly induced by retinoic acid in the ventral telencephalon, suggesting that RARbeta might be involved in retinoid signaling competence. The RT-PCR analysis indicated that RARbeta was selectively expressed in the developing striatum of ventral telencephalon. We then demonstrated that null mutations of RARbeta gene resulted in reduction of striatal-enriched tyrosine phosphatase (STEP) mRNA in the striatum of RARbeta-/- mutant mice. Conversely, the gain-of-function study showed that ectopic expression of RARbeta1 in the cerebral cortex enhanced STEP expression, and the effect was RARbeta-isoform specific. Our study identified RARbeta as an important molecule for transducing retinoid signals in developing ventral telencephalon.

Identification of a developmentally regulated striatum-enriched zinc-finger gene, Nolz-1, in the mammalian brain.

Neural information processed through the striatum of the basal ganglia is crucial for sensorimotor and psychomotor functions. Genes that are highly expressed in the striatum during development may be involved in neural development and plasticity in the striatum. We report in the present study the identification of a previously uncharacterized mammalian member of the nocA/elB/tlp-1 family, Nolz-1, that is preferentially expressed at high levels in the developing striatum. Nolz-1 mRNA was expressed as soon as striatal anlage began to form at embryonic day 13 in the rat. Nolz-1 mRNA was predominantly expressed in the lateral ganglionic eminence (striatal primordium) and was nearly absent in the adjacent structures of the medial ganglionic eminence and the cerebral cortex. Moreover, Nolz-1 was highly expressed in the subventricular zone of the lateral ganglionic eminence and was colocalized with the early neuronal differentiation markers of TuJ1 and Isl1 and the projection neuron marker of DARPP-32, suggesting that Nolz-1 was expressed in differentiating progenitors of striatal projection neurons. A time course study showed that Nolz-1 mRNA was developmentally regulated, as its expression was down-regulated postnatally with low levels remaining in the ventral striatum at adulthood. As the tagged Nolz-1 protein was localized in the nucleus, Nolz-1 may function as transcriptional regulator. In a model system for neural differentiation, Nolz-1 mRNA was dramatically induced on neural induction of P19 embryonal carcinoma cells by retinoic acid, suggesting that Nolz-1 activation may be involved in neural differentiation. Our study suggests that Nolz-1 is preferentially expressed in differentiating striatal progenitors and may be engaged in the genetic program for controlling striatal development.