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The Journal of Neuroscience, September 12, 2007, 27(37):9826-9834; doi:10.1523/JNEUROSCI.1710-07.2007

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Neurobiology of Disease
A Knock-In Reporter Model of Batten Disease

Steven L. Eliason,^1 * Colleen S. Stein,^1 * Qinwen Mao,¹ Luis Tecedor,¹ Song-Lin Ding,¹ D. Meredith Gaines,¹ and Beverly L. Davidson^1,2,3

Departments of ¹Internal Medicine, ²Neurology, and ³Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242

Correspondence should be addressed to Dr. Beverly L. Davidson, Department of Internal Medicine, 200 EMRB, University of Iowa, Iowa City, IA 52242. Email: beverly-davidson{at}uiowa.edu

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.

Key words: Batten disease; juvenile neuronal lipofuscinosis; JNCL; knock-in mouse; ß-galactosidase; lysosomal storage diseases; CLN3

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Received April 16, 2007; revised July 17, 2007; accepted July 18, 2007.

Correspondence should be addressed to Dr. Beverly L. Davidson, Department of Internal Medicine, 200 EMRB, University of Iowa, Iowa City, IA 52242. Email: beverly-davidson{at}uiowa.edu

This article has been cited by other articles:

				R. I. Tuxworth, V. Vivancos, M. B. O'Hare, and G. Tear Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways Hum. Mol. Genet., February 15, 2009; 18(4): 667 - 678. [Abstract] [Full Text] [PDF]

				C.-H. Chan, H. M. Mitchison, and D. A. Pearce Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models Hum. Mol. Genet., November 1, 2008; 17(21): 3332 - 3339. [Abstract] [Full Text] [PDF]

				C. Kitzmuller, R. L. Haines, S. Codlin, D. F. Cutler, and S. E. Mole A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis Hum. Mol. Genet., January 15, 2008; 17(2): 303 - 312. [Abstract] [Full Text] [PDF]

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