Developmental restriction of the LIM homeodomain transcription factor Islet-1 expression to cholinergic neurons in...

LIM homeodomain transcription factors play crucial roles in determining diverse aspects of neuronal development both in vertebrates and invertebrates. In the present study, we studied the expression pattern of Islet-1 (Isl-1), a member of the LIM homeodomain protein family, in the rat striatum during development. The developmental expression of Isl-1 in the striatum is highly dynamic and complex in terms of spatial and temporal regulation. The reverse transcription-polymerase chain reaction and ribonuclease protection assays demonstrated that Isl-1 messenger RNA was expressed in the developing striatum. The immunocytochemical study of Isl-1 protein expression showed that there were prominent mediolateral and caudorostral Isl-1 gradients in the developing striatum. Numerous Isl-1-positive cells appeared in the medial mantle zone of the developing striatal proper, and they co-expressed the postmitotic neuronal marker, microtubule-associated protein 2. The numbers of Isl-1-positive cells were decreased from the medial to the lateral regions, so that there were only a few Isl-1-positive cells scattered in the lateral striatum. These scattered Isl-1-positive cells were doubly labeled with tyrosine kinase receptor A and choline acetyltransferase, which indicated that they were cholinergic neurons. The Isl-1 gradients were most prominent in the embryonic day 18 and 20 striatum. With increases of time, the Isl-1 gradients were gradually reduced, and the gradients disappeared by postnatal day 7. Despite the general down-regulation of striatal Isl-1, a few Isl-1-positive cells were sustained into the adult striatum in which Isl-1 was nearly exclusively expressed by all cholinergic neurons and vice versa. Our study suggests that Isl-1 is likely to be initially expressed by postmitotic cholinergic precursors and some, if not all, non-cholinergic precursors in the developing striatum. During the progression of striatal differentiation, Isl-1 is down-regulated in non-cholinergic cells, but is sustained in cholinergic cells. The developmental restriction of Isl-1 to cholinergic neurons in the striatum may represent a novel mechanism by which LIM homeodomain proteins specify specific cell types in the striatum during development.