N-Methyl-d-aspartate Receptors Regulate a Group of Transiently Expressed Genes in the Developing Brain

Abstract

Long before synaptic networks are fully established, electrical activity present in developing neurons regulates neuronal differentiation (1-4). In particular, electrical activity mediated by the NMDA 1 class of glutamate receptors is required for normal neuronal development. Loss of NMDA receptor function during development increases neuronal cell death (5), prevents the formation of precise neural circuits (6, 7), diminishes respiration and feeding (8 -10), and has been implicated in fetal alcohol syndrome (11) and schizophrenia (12). NMDA receptor function can also regulate neuronal proliferation (13) and migration (14). Despite the importance of NMDA receptors for normal development and adult brain function, knowledge of molecular mechanisms regulated by NMDA receptors in developing neurons is rudimentary.Evidence from development as well as adult models of learning and memory indicate that regulation of gene expression is an important strategy that can be used to mediate changes in neuronal structure and function. Developmental studies suggest that mRNA abundance is rate-limiting for the accumulation of functional neurotransmitter receptors on neurons during development in vivo (15). Changes in gene expression also accompany activity regulated synaptic plasticity events in the developing visual system (16), as well as at the neuromuscular junction (17). Transcription factors have recently been shown to play a critical role for the development of synaptic connectivity (18 -20). Similarly, transcription may be required for activity dependent long term changes in synaptic strength in mature nervous systems (21-23). Finally, the electrical activity of neurons, including NMDA receptor function, has been shown to regulate gene expression in the adult hippocampus (24 -27), a structure critical for the establishment and maintenance of memories (28 -30).To test the hypothesis that NMDA receptor-dependent regulation of gene expression is required for, and directs, molecular and cellular mechanisms for neuronal development, we have designed a screen based on the neural circuit that connects highly specialized whiskers (mystacial vibrissae) found on the snout of the mouse to their synaptic targets in the brain stem. These whiskers are richly innervated by pseudounipolar sensory neurons of the trigeminal ganglion that project centrally to the brain stem trigeminal complex. Here synaptic inputs from the trigeminal ganglion that correspond to the mystacial vibrissae are organized in a pattern that matches their topographic organization on the face. This pattern of whisker representations, called barrelettes at the level of the brain stem, is relayed and reiterated in the thalamus and finally the cerebral cortex, and requires NMDA receptor function for normal development (8,10,31,32). The whisker representations are comparable to other sensory maps, for example, for touch, hearing, and vision, that are found in humans, and serve as a powerful mammalian model for highly patterned synaptic development and organization in viv...

NATH, a novel gene overexpressed in papillary thyroid carcinomas

“…The 5.5 kb NATH cDNA sequenced therefore represents the longer 5.8 kb mRNA incom- pletely sequenced in the 5'-untranslated region. In contrast, mouse Tbdn-1 mRNA was found to be 3.4 kb (Gendron et al, 2000), while Northern blot of mouse NARG1 mRNA (Sugiura et al, 2001) are consistent with our data. At the protein level, mouse Tbdn-1 was reported to be 69 kDa, suggested to result from an alternative translation initiation predicted to encode a protein of 594 amino acids.…”

“…These data, and the relative overexpression primarily in aggressive and dedifferentiated thyroid carcinomas suggest that NATH may be involved in cellular proliferation at some level. Interestingly, mouse tbdn-1 was expressed in M1 myeloid leukemia cells and was down-regulated during LIF-induced differentiation (Gendron et al, 2000), while mouse NARG-1 (mNAT1) was up-regulated in neonatal brain regions with neuronal proliferation, and further down-regulated by NMDA receptor activation (Sugiura et al, 2001). However, our NATH transfection experiments of papillary thyroid carcinoma (NPA) cells and 293 cells did not seem to alter the cellular proliferation rate.…”

“…The 5.5 kb NATH transcript harbored an open reading frame encoding a putative 866 amino acid protein, which was homologous to S. cerevisiae NAT1 (Mullen et al, 1989), mouse NARG1 (Sugiura et al, 2001), and to mouse Tbdn-1 (Gendron et al, 2000). The NATH protein contains four tetratricopeptide repeat (TPR) domains in two tandems.…”

“…Blast search showed the putative NATH protein to be homologous to Saccharomyces cerevisiae N-acetyltransferase (NAT)1 (Mullen et al, 1989) (854 amino acids, 25% identity). NATH is also homologous to the (partial) sequences of mouse NARG1 (Sugiura et al, 2001) and mouse Tubedown-1 (Tbdn-1) (Gendron et al, 2000) proteins, in the Nterminal and C-terminal parts, respectively (Figure 4). No evidence of alternatively spliced NATH transcripts affecting the open reading frame was detected from either PTC biopsies, or from the papillary carcinoma cell line NPA, in the RT -PCR experiments ( Figure 2c).…”

Molecular Characterization of NMDA-Like Receptors inAplysiaandLymnaea:Relevance to Memory Mechanisms

“…Finally, NMDA receptors also have additional recognition sites for polyamines (e.g., spermine that promotes receptor activation), for Zn 2ϩ (Peters et al, 1987;Westbrook and Mayer, 1987;Hollmann et al, 1993;Choi and Lipton, 1999;Fayyazuddin et al, 2000;Erreger and Traynelis, 2005;Hatton and Paoletti, 2005;Rachline et al, 2005), and for H ϩ (that acts to inhibit ion flux [Traynelis et al, 1995;Low et al, 2000]), as well as cysteine sites that can act as redox sensors (Sullivan et al, 1994;Choi et al, 2001). These characteristics of NMDA receptors, along with their widespread distribution in the mammalian nervous system, make them one of the major research targets of modern neuroscience (Cotman et al, 1988;Constantine-Paton et al, 1990;Daw et al, 1993;Sugiura et al, 2001;Wenthold et al, 2003).…”