title: Regulating the dorsal neural tube expression of Ptf1a through a distal 3' enhancer.
abstract: Generating the correct balance of inhibitory and excitatory neurons in a neural network is essential for normal functioning of a nervous system. The neural network in the dorsal spinal cord functions in somatosensation where it modulates and relays sensory information from the periphery. PTF1A is a key transcriptional regulator present in a specific subset of neural progenitor cells in the dorsal spinal cord, cerebellum and retina that functions to specify an inhibitory neuronal fate while suppressing excitatory neuronal fates. Thus, the regulation of Ptf1a expression is critical for determining mechanisms controlling neuronal diversity in these regions of the nervous system. Here we identify a sequence conserved, tissue-specific enhancer located 10.8kb 3' of the Ptf1a coding region that is sufficient to direct expression to dorsal neural tube progenitors that give rise to neurons in the dorsal spinal cord in chick and mouse. DNA binding motifs for Paired homeodomain (Pd-HD) and zinc finger (ZF) transcription factors are required for enhancer activity. Mutations in these sequences implicate the Pd-HD motif for activator function and the ZF motif for repressor function. Although no repressor transcription factor was identified, both PAX6 and SOX3 can increase enhancer activity in reporter assays. Thus, Ptf1a is regulated by active and repressive inputs integrated through multiple sequence elements within a highly conserved sequence downstream of the Ptf1a gene.
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Bishakha
authors.initials: B
authors.lastname: Mona
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Avila
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Meredith
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Kollipara
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address: jane.johnson@utsouthwestern.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D002531:Cerebellum / Q000196:embryology*; D002642:Chick Embryo; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D000071841:PAX6 Transcription Factor / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012160:Retina / Q000196:embryology; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013116:Spinal Cord / Q000196:embryology; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D000071841:PAX6 Transcription Factor; C000605732:Pax6 protein, mouse; D055748:SOXB1 Transcription Factors; C527786:Sox3 protein, mouse; D014157:Transcription Factors; C062602:transcription factor PTF1
keywords: Dorsal spinal cord; Inhibitory neurons; Neuronal specification; PTF1A; Tissue-specific enhancer; Transcriptional regulation