title: TDP-43 is a developmentally regulated protein essential for early embryonic development.
abstract: TDP-43 is a DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene expression. Alteration of this multifunctional protein is associated with a number of neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin positive inclusions. Whereas a pathological link to neurodegenerative disorders has been established, the cellular and physiological functions of TDP-43 remain unknown. In this study, we show that TDP-43 is a nuclear protein with persistent high-level expression during embryonic development and with progressively decreased protein levels during postnatal development. In mice where the TDP-43 gene (Tardbp) was disrupted using a gene trap that carries a beta-galactosidase marker gene, heterozygous (Tardbp(+/-)) mice are fertile and healthy, but intercrosses of Tardbp(+/-) mice yielded no viable homozygotic null (Tardbp(-/-)) mice. Indeed, Tardbp(-/-) embryos die between 3.5 and 8.5 days of development. Tardbp(-/-) blastocysts grown in cell culture display abnormal expansion of their inner cell mass. The pattern of beta-galactosidase staining at E9.5 Tardbp(+/-) embryos is predominantly restricted to the neuroepithelium and remains prominent in neural progenitors at E10.5-12.5. TDP-43 is detected in spinal cord progenitors and in differentiated motor neurons as well as in the dorsal root ganglia at E12.5. Beta-galactosidase staining of tissues from adult Tardbp(+/-) mice shows widespread expression of TDP-43, including prominent levels in various regions of the central nervous system afflicted in neurodegenerative disorders. These results indicate that TDP-43 is developmentally regulated and indispensible for early embryonic development.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Chantelle F
authors.initials: CF
authors.lastname: Sephton
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Good
authors.forename: Stan
authors.initials: S
authors.lastname: Atkin
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Dewey
authors.forename: Paul
authors.initials: P
authors.lastname: Mayer
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001755:Blastocyst / Q000473:pathology; D002490:Central Nervous System / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D019636:Neurodegenerative Diseases / Q000209:etiology; D009474:Neurons / Q000737:chemistry; D013234:Stem Cells / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D004268:DNA-Binding Proteins