A knock-in reporter model of Batten disease

Steven L. Eliason, Colleen S. Stein, Qinwen Mao, Luis Tecedor, Song Lin Ding, D. Meredith Gaines, Beverly L. Davidson*

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Juvenile neuronal ceroid lipofuscinosis is a severe inherited neurodegenerative disease resulting from mutations in CLN3 (ceroid- lipofuscinosis, neuronal 3, juvenile). CLN3 function, and where and when it is expressed during development, is not known. In this study, we generated a knock-in reporter mouse to elucidate CLN3 expression during embryogenesis and after birth and to correlate expression and behavior in a CLN3-deficient mouse. In embryonic brain, expression appeared in the cortical plate. In postnatal brain, expression was prominent in the cortex, subiculum, parasubiculum, granule neurons of the dentate gyrus, and some brainstem nuclei. In adult brain, reporter gene expression waned in most areas but remained in vascular endothelia and the dentate gyrus. Mice homozygous for Cln3 deletion showed two hallmark pathological features of the neuronal ceroid lipofuscinosises: autofluorescent inclusions and lysosomal enzyme elevation. Moreover, CLN3-deficient reporter mice displayed progressive neurological deficits, including impaired motor function, decreased overall activity, acquisition of resting tremors, and increased susceptibility to pentilentetrazole-induced seizures. Notably, seizure induction in heterozygous mice was accompanied by enhanced reporter expression. This model provides us with the unique ability to correlate expression with pathology and behavior, thus facilitating the elucidation of CLN3 function and the pathogenesis of Batten disease.

Original languageEnglish (US)
Pages (from-to)9826-9834
Number of pages9
JournalJournal of Neuroscience
Volume27
Issue number37
DOIs
StatePublished - Sep 12 2007

Keywords

  • Batten disease
  • CLN3
  • JNCL
  • Juvenile neuronal lipofuscinosis
  • Knock-in mouse
  • Lysosomal storage diseases
  • β-galactosidase

ASJC Scopus subject areas

  • Neuroscience(all)

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    Eliason, S. L., Stein, C. S., Mao, Q., Tecedor, L., Ding, S. L., Gaines, D. M., & Davidson, B. L. (2007). A knock-in reporter model of Batten disease. Journal of Neuroscience, 27(37), 9826-9834. https://doi.org/10.1523/JNEUROSCI.1710-07.2007