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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047710-03
Application #
7012191
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Leblanc, Gabrielle G
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$327,166
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Prescott, Steven A; Ma, Qiufu; De Koninck, Yves (2014) Normal and abnormal coding of somatosensory stimuli causing pain. Nat Neurosci 17:183-91
Duan, Bo; Cheng, Longzhen; Bourane, Steeve et al. (2014) Identification of spinal circuits transmitting and gating mechanical pain. Cell 159:1417-1432
Xu, Yi; Lopes, Claudia; Wende, Hagen et al. (2013) Ontogeny of excitatory spinal neurons processing distinct somatic sensory modalities. J Neurosci 33:14738-48
Roberson, David P; Gudes, Sagi; Sprague, Jared M et al. (2013) Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat Neurosci 16:910-8
Liu, Tong; Berta, Temugin; Xu, Zhen-Zhong et al. (2012) TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest 122:2195-207
Mar, Lynn; Yang, Fu-Chia; Ma, Qiufu (2012) Genetic marking and characterization of Tac2-expressing neurons in the central and peripheral nervous system. Mol Brain 5:3
Ma, Qiufu (2012) Population coding of somatic sensations. Neurosci Bull 28:91-9
Liu, Yang; Ma, Qiufu (2011) Generation of somatic sensory neuron diversity and implications on sensory coding. Curr Opin Neurobiol 21:52-60
Ma, Qiufu (2010) Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest 120:3773-8
Ross, Sarah E; Mardinly, Alan R; McCord, Alejandra E et al. (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65:886-98

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