The mammalian nervous system is composed of thousands of distinct neuronal cell types. However, all of them are either excitatory or inhibitory. The principal excitatory and inhibitory neurotransmitters are the amino acids glutamate and GABA (gamma-aminobutyrate), respectively. During development, these two transmitters are specified in a mutually exclusive manner. The broad goal of this proposal is to understand the molecular mechanism that underlies this very important fate choice decision. In preliminary studies, we have focused upon an anatomically well-defined region of the developing nervous system - the dorsal horn of the spinal cord. We have found that the Tlx-class transcription factors have a dual function in cell fate choice: promoting glutamate and suppressing GABA neuron development. Thus, in Tlx-null mice, glutamatergic sensory cells in the dorsal horn are transformed into GABAergic neurons. Our study plan builds upon this preliminary data. We have three specific aims.
Aim 1 is to define the anatomical range of Tlx function in the glutamatergic versus GABAergic fate choices. Is this Tlx function confined to the dorsal horn of the spinal cord or does it extend to other Tlx-positive regions of the central nervous system - specifically, the sensory nuclei in the hindbrain? Addressing this question will determine whether binary specification of glutamate and GABA is a common theme in the nervous system and may also provide insight into why Tlx-null mice suffer a breathing problem that resembles human congenital hypoventilation syndrome.
Aim 2 is to define the roles of Tlx proteins in the fate choice process. Our preliminary studies show that Tlx proteins are necessary for glutamate neuron development. Here we will use genetic gain-of-function to determine whether Tlx proteins are sufficient to specify glutamate transmitter phenotype in various brain areas. In addition, we will determine whether Tlx proteins directly or indirectly promote glutamatergic neuron differentiation.
Aim 3 is to define the structural basis of Tlx proteins in suppression of GABA neuron differentiation. Within the human CNS, a disruption of the balance between excitation and inhibition underlies neurological disorders, such as epilepsy, schizophrenia, and pain disorders. Accordingly the studies described here will have practical overtones for the management of these diseases.
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