TDP-43 is a developmentally regulated protein essential for early embryonic development

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.
• These results indicate that TDP-43 is developmentally regulated and indispensible for early embryonic development.

Why it matters

Mice lacking the TDP-43 gene died early in embryonic development, showing the protein is required for normal development. This is animal developmental biology and does not test any treatment, cure or prevention for Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.m109.061846
• PubMed: 20040602
• Original source →
• Free full text: Journal of Biological Chemistry →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{sephton2010-20040602,
  author  = {Sephton, C. F. and Good, S. K. and Atkin, S. and Dewey, C. M. and Mayer, P. and Herz, J. and Yu, G.},
  title   = {{TDP-43 is a developmentally regulated protein essential for early embryonic development}},
  journal = {The Journal of biological chemistry},
  year    = {2010},
  doi     = {10.1074/jbc.m109.061846},
  pmid    = {20040602},
  url     = {https://doi.org/10.1074/jbc.m109.061846}
}

Studies this one cites

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• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases Acta neuropathologica · 2007-07-25 · usefulness score 59/100 · How common it is
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · Lewy body dementia
• Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America · 2009-04-21 · usefulness score 55/100 · Lewy body dementia
• TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2009-10-15 · usefulness score 52/100 · Lewy body dementia
• Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies The Journal of biological chemistry · 2009-01-21 · usefulness score 51/100 · Lewy body dementia

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• TDP-43 proteinopathies: a new wave of neurodegenerative diseases Journal of neurology, neurosurgery, and psychiatry · 2020-11-11 · usefulness score 54/100 · Lewy body dementia
• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100 · Lewy body dementia

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