The mature CNS is comprised of a multitude of different neuronal subtypes. This diversity in neuronal subtypes is fundamental to the many complex functions that the CNS controls. The generation of neuronal diversity in the developing CNS seems to be controlled by localized production of neuronal subtypes and the subsequent distribution of these subtypes within the brain via migration. Localized neuronal generation is dependent on the formation and output of discrete neuronal progenitor domains. This proposal will focus on two such progenitor domains in the lateral ganglionic eminence (LGE) of the telencephalon. This region of the developing brain gives rise to the projection neurons of the striatum as well as interneurons in the olfactory bulb. Gene expression studies have suggested that the LGE can be divided into a dorsal (dLGE) and ventral (vLGE) domain. The dLGE expresses the ETS transcription factor gene Er81 while the vLGE is marked by the LIM homeobox gene Islet1 (Isl1). We have recently identified a new marker of the dLGE called Sp8, which is a new member of the Sp1 transcription factor family. Our previous work led us to propose that the dLGE and vLGE give rise to distinct neuronal progeny, namely the olfactory bulb intemeurons and striatal projection neurons, respectively. The main goal of this proposal is to test this hypothesis by the experiments outlined in the following 3 specific aims.
Specific aim 1 will use genetic fate mapping to follow the neurons derived from either the Isl1-expressing-vLGE or the Sp8-expressing dLGE.
Specific Aim 2 will determine the role of Sp8 in dLGE and olfactory bulb interneuron development using conditional mutagenesis and over-expression. Finally, Specific Aim 3 will examine the requirement of Isl1 for vLGE development using conditional mutagenesis and over-expression both in vivo and in vitro. Many neuro-psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), Tourette's syndrome and Schizophrenia, which affect children and young adults, are thought to result, at least in part, from abnormal striatal function. Recent thinking supports the idea that these brain disorders may be due, at least in part, to abnormalities of brain development. Thus knowledge of the mechanisms that regulate neuronal diversity in the LGE is likely to contribute to a better understanding and possibly treatments of these brain disorders.
