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J. Biol. Chem., Vol. 280, Issue 11, 10100-10108, March 18, 2005

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Transcriptional Activity of the Paired-like Homeodomain Proteins CHX10 and VSX1^*

Kimberley M. Dorval¶||, Brian P. Bobechko¶, K. Farid Ahmad, and Rod Bremner¶**

From the Toronto Western Research Institute, University Health Network Program, Departments of Laboratory Medicine and Pathobiology and ^**Ophthalmology and Visual Sciences, ^¶Vision Science Research Program, University of Toronto, Toronto, Ontario M5T 2S8, Canada

CHX10 and VSX1 are homeodomain (HD) proteins essential for normal retinal development. CHX10 is required first for retinal progenitor cell proliferation and later for bipolar cell differentiation, whereas VSX1 is important in the terminal differentiation of a subset of bipolar cells. Elucidating the transcriptional activity of CHX10 and VSX1 is required to understand how these factors control retinal development. We show that CHX10 and Vsx1 can function as transcriptional repressors. When tethered to a promoter by a heterologous LexA DNA-binding domain or its HD, CHX10 repressed multiple classes of activators in different immortalized cell lines. CHX10 blocked TATA-containing and TATA-less promoters, repressed at a distance, and inhibited a complex enhancer positioned upstream or downstream of the reporter gene, whereas retinoblastoma protein (RB) inhibited the downstream enhancer only. Interestingly, CHX10 mildly potentiated a subset of activators in chick neuronal cultures. Thus, CHX10 is both a versatile repressor and a context-specific weak activator. The CHX10 HD and CVC domains were sufficient for DNA binding and repression. VSX1 contains closely related homeo and CVC domains and, like CHX10, also repressed transcription. A VSX1 HD mutation, R166W, that impairs DNA binding and causes keratoconus in humans, hindered repressor function. Therefore, CHX10 and VSX1 may control retinal bipolar cell specification or differentiation by repressing genes required for the development of other cell types.

Received for publication, November 9, 2004 , and in revised form, January 7, 2005.

^* This work was supported in part by a grant from the Canadian Institute for Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Recipient of a Vision Science Research Program Doctoral Research Award (Toronto, Canada) and an E. A. Baker Foundation and The Canadian National Institute for the Blind/Canadian Institute for Health Research Partnership Doctoral Research Fellowship.

To whom correspondence should be addressed: Toronto Western Research Institute, Mc6–424, Cellular and Molecular Division, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada. Tel.: 416-603-5865; Fax: 416-603-5126; E-mail: rbremner{at}uhnres.utoronto.ca.

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