An increasing number of diseases of the brain are being linked to deviations from the normally carefully calibrated balance between excitatory and inhibitory neuronal activities. A critical choice point for establishing this inhibitory/excitatory neuronal balance is governed by the transcription factor Ptf1a. Ptf1a is a bHLH transcription factor that is required for GABAergic inhibitory neurons in the dorsal spinal cord, cerebellum, and retina. In the absence of Ptf1a, neural progenitor cells fail to generate inhibitory neurons and aberrantly assume an excitatory neuronal phenotype. Uncovering the transcriptional control of Ptf1a expression and the function of its downstream targets will provide molecular insight into developmental processes regulating the neuronal circuitry in multiple regions of the central nervous system. Because of the timing and the mechanism of PTf1a function, it provides a unique opportunity to uncover the molecular mechanisms that couple neuronal differentiation and neuronal subtype specification. Identification of cis-regulatory sequences in the Ptf1a gene locus revealed separable elements controlling transcription initiation, autoregulation, restriction to dI4/dIL progenitors, and downregulation as the cells differentiate to inhibitory neurons. In addition, direct targets of Ptf1a have been identified that serve as candidates for mediating inhibitory neuronal identity while suppressing excitatory neuron identity. The goal of the current project is to build on these findings to 1) identify trans-acting upstream factors and signaling pathways that function through the cis-regulatory sequences to regulate Ptf1a, and 2) determine the function of a downstream target of Ptf1a in specification of interneurons in the dorsal horn, cerebellum, and retina. Success in this program will impact understanding of how stem/progenitor cells transition to mature cell types and generate the neuronal diversity required for circuit formation. Identifying the pathways that direct cells down a specific lineage may have therapeutic value in stem cell manipulation and treatment of neurological disorders.

Public Health Relevance

Alterations in the balance of inhibitory and excitatory neurons are thought to underlie diverse neurological disorders from epilepsy to autism to hyperalgesia. Ptf1a is an essential regulator of this balance in multiple regions of the nervous system, and thus, factors and signaling pathways regulating Ptf1a and regulated by Ptf1a will control the formation of these balanced neuronal networks. Pathways identified here may serve as targets for manipulating the fate of stem cells for regenerative purposes, and are likely to provide fundamental principles of gene regulation common to developing systems.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD037932-14
Application #
8644810
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Henken, Deborah B
Project Start
2000-06-01
Project End
2016-01-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
14
Fiscal Year
2014
Total Cost
$328,415
Indirect Cost
$121,865
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Borromeo, Mark D; Meredith, David M; Castro, Diogo S et al. (2014) A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord. Development 141:2803-12
Chang, Joshua C; Meredith, David M; Mayer, Paul R et al. (2013) Prdm13 mediates the balance of inhibitory and excitatory neurons in somatosensory circuits. Dev Cell 25:182-95
Meredith, David M; Borromeo, Mark D; Deering, Tye G et al. (2013) Program specificity for Ptf1a in pancreas versus neural tube development correlates with distinct collaborating cofactors and chromatin accessibility. Mol Cell Biol 33:3166-79
Tran, Tracy S; Carlin, Edward; Lin, Ruihe et al. (2013) Neuropilin2 regulates the guidance of post-crossing spinal commissural axons in a subtype-specific manner. Neural Dev 8:15
Johnson, Jane E; Macdonald, Raymond J (2011) Notch-independent functions of CSL. Curr Top Dev Biol 97:55-74
Kim, Euiseok J; Hori, Kei; Wyckoff, Alex et al. (2011) Spatiotemporal fate map of neurogenin1 (Neurog1) lineages in the mouse central nervous system. J Comp Neurol 519:1355-70
Quinones, Herson I; Savage, Trisha K; Battiste, James et al. (2010) Neurogenin 1 (Neurog1) expression in the ventral neural tube is mediated by a distinct enhancer and preferentially marks ventral interneuron lineages. Dev Biol 340:283-92
Meredith, David M; Masui, Toshihiko; Swift, Galvin H et al. (2009) Multiple transcriptional mechanisms control Ptf1a levels during neural development including autoregulation by the PTF1-J complex. J Neurosci 29:11139-48
Henke, R Michael; Savage, Trisha K; Meredith, David M et al. (2009) Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development 136:2945-54
Hori, Kei; Cholewa-Waclaw, Justyna; Nakada, Yuji et al. (2008) A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling. Genes Dev 22:166-78

Showing the most recent 10 out of 15 publications