TY - JOUR
T1 - TDP-43 is a developmentally regulated protein essential for early embryonic development
AU - Sephton, Chantelle F.
AU - Good, Shannon K.
AU - Atkin, Stan
AU - Dewey, Colleen M.
AU - Mayer, Paul
AU - Herz, Joachim
AU - Yu, Gang
PY - 2010/2/26
Y1 - 2010/2/26
N2 - 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 β-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 β-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. β-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.
AB - 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 β-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 β-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. β-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.
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U2 - 10.1074/jbc.M109.061846
DO - 10.1074/jbc.M109.061846
M3 - Article
C2 - 20040602
AN - SCOPUS:77949878273
SN - 0021-9258
VL - 285
SP - 6826
EP - 6834
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 9
ER -