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The Journal of Neuroscience, December 20, 2006, 26(51):13167-13179; doi:10.1523/JNEUROSCI.4238-06.2006

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Development/Plasticity/Repair
Deletion of the Ttf1 Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function

Claudio Mastronardi,^1 * Gregory G. Smiley,^1 * Jacob Raber,^1,2 Takashi Kusakabe,³ Akio Kawaguchi,³ Valerie Matagne,¹ Anja Dietzel,⁴ Sabine Heger,⁴ Alison E. Mungenast,¹ Ricardo Cabrera,¹ Shioko Kimura,³ and Sergio R. Ojeda¹

¹Division of Neuroscience, Oregon National Primate Research Center/Oregon Health & Science University, Beaverton, Oregon 97006, ²Departments of Behavioral Neurosciences and Neurology, Oregon Health & Science University, Portland, Oregon 97239, ³Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and ⁴Hospital for Children and Adolescents, University of Leipzig, 04317 Leipzig, Germany

Correspondence should be addressed to Sergio R. Ojeda, Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006. Email: ojedas{at}ohsu.edu

Thyroid transcription factor 1 (TTF1) [also known as Nkx2.1 (related to the NK-2 class of homeobox genes) and T/ebp (thyroid-specific enhancer-binding protein)], a homeodomain gene required for basal forebrain morphogenesis, remains expressed in the hypothalamus after birth, suggesting a role in neuroendocrine function. Here, we show an involvement of TTF1 in the control of mammalian puberty and adult reproductive function. Gene expression profiling of the nonhuman primate hypothalamus revealed that TTF1 expression increases at puberty. Mice in which the Ttf1 gene was ablated from differentiated neurons grew normally and had normal basal ganglia/hypothalamic morphology but exhibited delayed puberty, reduced reproductive capacity, and a short reproductive span. These defects were associated with reduced hypothalamic expression of genes required for sexual development and deregulation of a gene involved in restraining puberty. No extrapyramidal impairments associated with basal ganglia dysfunction were apparent. Thus, although TTF1 appears to fulfill only a morphogenic function in the ventral telencephalon, once this function is satisfied in the hypothalamus, TTF1 remains active as part of the transcriptional machinery controlling female sexual development.

Key words: TTF1; homeobox genes; conditional gene deletion; hypothalamus; basal ganglia; female puberty

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Received July 19, 2006; revised Nov. 2, 2006; accepted Nov. 4, 2006.

Correspondence should be addressed to Sergio R. Ojeda, Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006. Email: ojedas{at}ohsu.edu

This article has been cited by other articles:

				C. L. Roth, C. Mastronardi, A. Lomniczi, H. Wright, R. Cabrera, A. E. Mungenast, S. Heger, H. Jung, C. Dubay, and S. R. Ojeda Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty Endocrinology, November 1, 2007; 148(11): 5147 - 5161. [Abstract] [Full Text] [PDF]

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