TDP-43 Is a Developmentally Regulated Protein Essential for Early Embryonic Development*

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

Longitudinal Functional Study of Murine Aging: A Resource for Future Study Designs

ABSTRACT Aging is characterized by systemic declines in tissue and organ functions. Interventions that slow these declines represent promising therapeutics to protect against age‐related disease and improve the quality of life. In this study, several interventions associated with lifespan extension in invertebrates or improvement of age‐related disease were tested in mouse models to determine if they were effective in slowing tissue aging in a broad spectrum of functional assays. Benzoxazole, which extends the lifespan of Caenorhabditis elegans, slowed age‐related femoral bone loss in mice. Rates of change were established for clinically significant parameters in untreated mice, including kyphosis, blood glucose, body composition, activity, metabolic measures, and detailed parameters of skeletal aging in bone. These findings have implications for the study of preclinical physiological aging and therapies targeting aging. Finally, an online application was created that includes the calculated rates of change and that enables power and variance to be calculated for many clinically important metrics of aging with an emphasis on bone. This resource will help in future study designs employing novel interventions in aging mice. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research