The mammalian telencephalon represents the region of the brain that displays the most cellular diversity, particularly with respect to neuronal subtypes. One likely mechanism for generating this diversity is its protracted schedule of neurogenesis. Indeed, telencephalic neurogenesis continues postnatally and even into adulthood, at least in the olfactory bulb and hippocampus. This proposal will examine the role of two homeobox genes, Gsh1 and Gsh2 and their role in the neurogenesis of striatal projection neurons and olfactory bulb interneurons. While striatal neurogenesis occurs exclusively at embryonic time points, olfactory bulb interneurons are generated at both embryonic and postnatal stages. Recent work has found that Gsh2-expressing progenitors also give rise to oligodendrocytes at perinatal stages, this correlates with the period when Gsh2 is down-regulating. We hypothesize that Gsh genes promote neurogenesis in the embryonic and postnatal brain while repressing oligodendrocyte development. The four aims in this proposal are designed to address this hypothesis.
The first aim, will examine the time windows in which Gsh2 specifies striatal projection neuron progenitors and their olfactory bulb interneuron counterparts as well as it negative regulation of oligodendrocyte specification during embryogenesis.
The second aim will examine the role of Gsh1 in promoting differentiation of telencephalic progenitors.
Aim 3 will examine the role of Mash1 and Dlx1/2 genes down-stream of Gsh2 in telencephalic development. Finally, aim 4 will examine the requirement for Gsh genes in regulating neurogenesis and oligodendrogenesis within the postnatal subventricular zone. Certain neurodevelopmental disorders such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) are thought to result at least in part from abnormal function/development of the striatum. Additionally, the fact that olfactory bulb interneurons are generated into adulthood has made their progenitors attractive candidates for cellular engineering and cell replacement therapies. Thus greater knowledge of striatal and olfactory bulb development and the specific roles that Gsh genes play in these processes is likely to provide a better understanding of certain brain disorders and possible brain repair strategies.

Public Health Relevance

The telencephalon represents the region of the brain most concerned with cognition and voluntary movement. One of the major telencephalic structures controlling these processes is the striatum (also known as the caudate-putamen). Malfunction of the striatum occurs in a number of neurodegenerative disorders such as Parkinson's disease and Huntington's chorea, leading to abnormal movements and in some cases dementia. Moreover, certain neurodevelopmental disorders, such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) have been suggested to result from malfunction and/or altered development of the striatum. The embryonic region that gives rise to the striatal projection neurons also produces interneurons that migrate rostrally to the olfactory bulb. Unlike the striatal projection neurons, the olfactory bulb interneurons are continuously produced throughout the lifetime of the animal. This fact has led to a growing field of research, which is attempting to isolate and characterize the neural stem cells that generate these neurons in the adult brain. The hope of these studies is that the stem cells could be used for cell replacement strategies in certain neurodegenerative diseases (e.g. Parkinson's and Huntington's disease). Little is known, however, about the specification of either striatal projection neurons or olfactory bulb interneurons. Thus greater knowledge as to the molecular mechanisms (e.g. Gsh1 and Gsh2) underlying the generation of these two neuronal subtypes is likely to contribute to a better understanding of the above mentioned brain disorders as well as providing possibilities for brain repair strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-J (02))
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Riddle, Robert D
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Cincinnati Children's Hospital Medical Center
United States
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