QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Summary Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ikeda, A. Articles by Naggert, J. K. Search for Related Content PubMed PubMed Citation Articles by Ikeda, A. Articles by Naggert, J. K. Social Bookmarking                         What's this?

The tubby-like proteins, a family with roles in neuronal development and function

The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA

*Author for correspondence (e-mail: jkn{at}jax.org)

	SUMMARY

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
The identification of a mutation at the tubby (Tub) locus, which causes obesity and neurosensory degeneration, led to the discovery of the tubby-like proteins (TULPs). Tub and the genes that encode three tubby-like proteins (TULP1- TULP3) form a novel, small gene family that plays an important role in maintenance and function of neuronal cells during development and post-differentiation. Although exploration of the molecular function of these genes is still in its infancy, recent biochemical studies have provided ‘entry points’ into pathways whose elucidation will further our understanding of TULP action. In addition, mRNA expression and translocation of the TUB protein have been shown to be regulated by thyroid hormone and by G-protein-coupled receptor signaling, respectively. These latter findings may help to link the cellular function of TUB to known mechanisms for energy homeostasis.

Key words: Tubby, Tubby-like protein, neuron

	Introduction

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
Currently, four tubby gene family members (Tub, Tulp1, Tulp2 and Tulp3) (Kleyn et al., 1996; Noben-Trauth et al., 1996; North et al., 1997; Nishina et al., 1998) have been identified in humans and mice. These four genes probably comprise the entire vertebrate family because only one gene has been found in Drosophila (GenBank accession number: AE003453) and C. elegans (AF143297), which is consistent with the proposed two genome duplications that occurred during vertebrate evolution (Gibson and Spring, 2000). Tubby-like genes are also found in other organisms (i.e. Gallus (AJ396643), Xenopus (AW638855), Zea Mays (AI737314) and Arabidopsis (AC005309)). Plants in particular appear to harbor a large number of tubby-like proteins (TULPs). The strong conservation of Tub across members (Fig. 1) and through evolution suggests that the TULPs carry out some basic function in cells in which they are expressed. This suggestion is strengthened by the occurrence of disease phenotypes that result from mutations within tub and Tulp1 (Kleyn et al., 1996; Noben-Trauth et al., 1996; Heckenlively et al., 1995; Ohlemiller et al., 1997; Hagstrom et al., 1998; Banerjee et al., 1998; Lewis et al., 1999; Paloma et al., 2000) and by the embryonic lethality of mice homozygous for a disrupted Tulp3 allele (Ikeda et al., 2001).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Organization of the TUB, TULP3 and TULP1 proteins. Each box represents amino acids translated from each exon, and the percentage amino-acid sequence similarity with TUB is shown. Green boxes indicate the N-terminal regions with relatively low homology between family members. Red boxes indicate the C-terminal regions with high homology. The blue boxes represent the common acceptor site for alternative N-terminal exons observed in both human and mouse TUB. Yellow and pink boxes represent exons that are not conserved among family members. The nuclear localization signal is indicated. The N-terminal regions of TUB and TULP1 are able to activate transcription; the C-terminal region of TUB can bind to double-stranded DNA and to phosphatidylinositol-phosphates.

	TULPs are important for normal neuronal function in animals

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
The original phenotype associated with a mutation in the Tub gene, maturity onset obesity associated with insulin resistance (Table 1) (Coleman and Eicher, 1990), was later expanded to include sensory neural defects (retinal and cochlear degeneration) (Heckenlively et al., 1995; Ohlemiller et al., 1997). As the tubby gene is predominantly expressed in neuronal cells, including those of the hypothalamus, it was suggested that the late-onset obesity in tubby mice might reflect defects in the neurons of the hypothalamic ‘satiety center’ (Kleyn et al., 1996). Pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) mRNA levels are significantly reduced in the arcuate nucleus (ARC), whereas NPY levels are increased 30-fold in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei of tubby mice compared with wild-type controls (Guan et al., 1998). Although a reduction in MSH (melanin-stimulating hormone), an anorexigenic peptide derived from POMC, might be expected to result in increased body weight, the consequences of increased NPY levels in the VMH and DMH are not known. In addition, the MSH expression changes were observed after the disease onset and, therefore, may not be causative. The exact role of TUB in the etiology of the obese phenotype thus remains unclear. As TUB is expressed at comparable levels in all neurons in the brain, it is possible that additional, more subtle, phenotypes remain to be discovered.

Unlike tubby and Tulp1^–/– mice, B6.129-Tulp3^tm1Jax (Tulp3^–/–) mice exhibit embryonic lethality, with failure of neural tube closure characterized by neuroepithelial apoptosis, specifically in the hindbrain and the caudal neural tube (Ikeda et al., 2001). Tulp3 is ubiquitously expressed throughout embryonic development. The earliest observable phenotype of the knockout mice is a significant reduction in the number of ßIII-tubulin-positive neurons in the hindbrain at embryonic days (E) 9.5-10.5. Tulp3 appears, therefore, to be essential for the maintenance or function of normally differentiating neuronal cell populations. The neuroepithelial cell population is known to be spatially subdivided into distinct classes of neuron (Briscoe and Ericson, 2001). As apoptosis is restricted to the ventral region of the neuroepithelium in the hindbrain of Tulp3^–/– embryos, there is selective cell death in specific cell types in this targeted mutant model.

Taken together, the genetic analyses suggest that the primary site of action of the tubby family genes is in neuronal cells, including hypothalamic, sensory and differentiating embryonic neurons. ‘Apoptosis’ of neuronal cells is common to all mutations in tubby family genes. Do mutations within Tulp genes directly drive the cell death pathway or does a functional defect lead to the eventual cell death? In the case of the sensory neural defects, the latter alternative is likely. Auditory brainstem response (ABR) and electroretinographic (ERG) recordings in tubby mice show a functional loss of hearing and vision, respectively, before cell death (Ikeda et al., 1999a) (A.I. et al., unpublished).

	Gene-gene interactions determine the tubby phenotype

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
The severity of the phenotypes observed in tubby mice is affected by the genetic background (Ikeda et al., 1999a; Nishina et al., 2000). For example, the profound hearing loss in B6-tub/tub mice is completely rescued in tub/tub homozygous progeny derived from intercrossing B6-tub/tub mice with the mouse strains AKR/J, CAST/Ei and 129/Ola. Linkage analysis identified a major modifier locus – modifier of tubby hearing 1 (moth1) (Ikeda et al., 1999). A single moth1 allele from several different inbred strains protects tubby mice from the hearing loss associated with a B6-derived recessive moth1 allele. Homozygosity of the B6 moth1 allele itself cannot induce hearing impairment in wild-type B6 mice. This suggests that the allelic difference in the moth1 gene of B6 compared to the other inbred strains, therefore, is not critical for maintaining their sensory neurons but becomes significant only when the tubby gene is mutated and unable to function properly. In addition, the moth1 locus maps to a region on mouse chromosome 2 that also contains a gene that protects tubby mice from retinal degeneration (Nishina et al., 2000). This finding suggests that the same gene on chromosome 2 is involved in a common pathway through which retinal and cochlear degeneration are induced in tubby mice.

	Molecular structure and genetic studies suggest a common functional domain among TULPs

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
The C-terminal region is highly conserved among TULPs (Fig. 1), suggesting that this region might contain a functionally important domain. This idea is supported by genetic studies. The mutation within the tub gene is at a splice donor site in the last intron, which results in the replacement of the last 44 amino-acid residues with 24 that are not observed in the normal protein (Kleyn et al., 1996; Noben-Trauth et al., 1996). The fact that the targeted tub null allele (Stubdal et al., 2000) has the same phenotype as the spontaneous mutant confirms that this splice-site mutation is also the molecular basis for the spontaneous loss-of-function mutation. In addition, the same type of splice-site mutation was observed in the TULP1 gene among patients affected with retinitis pigmentosa (RP) 14 in a large Dominican Republic kindred (Banerjee et al., 1998). A clustering of mutations in the C-terminal region was also found in spontaneous cases of RP, again emphasizing the functional importance of this domain in Tubby family members.

To probe the function of this conserved region, Boggon et al. (Boggon et al., 1999) crystallized the C-terminal domain of TUB and performed X-ray crystallographic analyses. The electron-density map obtained was interpreted as a unique protein structure, a 12-stranded ß-barrel conformation filled with a central hydrophobic core that traverses the entire barrel. Two prominent features of the folded protein are a large groove of positively charged residues and a smaller region of negatively charged residues on the opposite side of the groove. This positively charged groove is expected to form protein-protein or protein-DNA binding sites. Additional molecular biological experiments showed that the TUB C-terminal domain has the potential to bind double-stranded DNA oligomers (Boggon et al., 1999). Given that a chimeric protein composed of the N-terminus of TUB or TULP1 and a GAL4 DNA-binding domain can activate transcription, Boggon et al. (Boggon et al., 1999) suggested that TUB might be a novel class of transcription factor (Fig. 2b). So far, there is no experimental evidence that TUB or TULP1 can recognize specific DNA sequences, and targets for TUB transcriptional activation have not yet been identified. Nevertheless, it is tempting to speculate that the reduced Pomc and Npy mRNA levels in the arcuate nucleus are the result of reduced TUB transcriptional activity in the tubby mutant.

View larger version (40K): [in this window] [in a new window]   Fig. 2. Proposed molecular functions of TULPs. (a) TUB as a mediator of insulin signaling. TUB is phosphorylated by the insulin receptor kinase domain, as well as by ABL and JAK2. This phosphorylation increases the binding capacity of TUB for proteins that have SH2 domains, such as PLC-. (b) TUB as a nuclear signaling molecule. TUB is attached to the plasma membrane through PtdIns(4,5)P2. The signals from G-protein-coupled receptors phosphorylate Gq and release TUB through PLC-ß activity. TUB released from the plasma membrane is translocated to the nucleus where it may act as a transcription factor. (c) TUB as a facilitator of rhodopsin transport in rod photoreceptors. The rod photoreceptor structure has five distinct components: the rod outer segment (OS) containing membrane discs stacked within a plasma membrane envelope; the inner segment (IS) containing the biosynthetic machinery; the connecting cilium (CC) joining the OS and IS; the cell body containing the nucleus; and the spherule representing the synaptic ending of the cell (Tai et al., 1999). Rhodopsin is manufactured in the Golgi apparatus of the IS and packaged into vesicles. The C-terminal tail of opsin interacts with the dynein light chain and is transported along microtubules to the cilium where the rhodopsin-containing vesicles fuse with the plasma membrane. Rhodopsin is then thought to be transported to the outer segment (blue arrows) by kinesin-II (Tai et al., 1999; Marszalek et al., 2000). In Tulp1–/– mice, mislocalization of rhodopsin is observed in the plasma membrane (red arrows). Since TULP1 is localized in the IS, it may be involved in the transport the vesicles containing rhodopsin.

Protein sequences are highly conserved among tubby gene family members, which suggests that they perform the same type of function within the cells in which they are expressed. As described below, the observed mislocalization of rhodopsin in both tubby and Tulp1^–/– mice implies a common function (Hagstrom et al., 1999; Hagstrom et al., 2001) (A.I., P.M.N. and J.K.N., unpublished data). However, although expression of each gene appears to overlap in several cell types, genetic analyses suggest that they are not functionally redundant in all tissues. Although both TUB and TULP1 are expressed in the same hypothalamic neurons, tubby mice become obese but Tulp1^–/– mice do not, which suggests unique tasks for each protein (Ikeda et al., 2000). This idea is also supported by the observation that the distribution of TUB and TULP1 within the nucleus of hypothalamic neurons is not overlapping (Ikeda et al., 2000). In Tulp3^–/– embryos, only a specific population of neuronal cells undergoes apoptosis. One explanation for the restricted cell death is that the ubiquitously expressed Tulp3 is interacting with specific genes in a subset of developing neuronal cells. Alternatively, although on an organismal level there does not appear to be functional redundancy, it remains possible that family members can substitute for each other in specific cell types. In this context, it is interesting that abnormalities are observed only in adult tub/tub mice, even though the Tub gene is highly expressed in the neuroepithelium at embryonic day E10.5 (Sahly et al., 1998), a time at which the Tulp3 gene is also expressed (Ikeda et al., 2001). It is possible, therefore, that Tulp3 compensates for TUB during neuronal cell development.

	Thyroid hormones T3 and T4 regulate Tub expression

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
Koritschoner et al. (Koritschoner et al., 2001) identified Tub as a potential T3-regulated gene in a differential display experiment. The level of expression of Tub is lower in hypothyroid rats, most significantly in Purkinje cells of the cerebellum. Normal expression levels were restored by T3/T4 treatment. Tub expression was also upregulated by T3 treatment of cultured neuronal cells. These results suggest that the expression of Tub is regulated by thyroid hormone, a hormone known to be important in the regulation of body weight (Krotkiewski, 2000) and neurosensory development (Forrest et al., 1996; Ng et al., 2001). However, the significance of these findings, although interesting, is not yet readily apparent, because the major difference in expression levels was observed in Purkinje cells. Although a role for the cerebellum in food intake operant behavior has been suggested (Morimoto et al., 1984; Lucchi et al., 1998; Mahler et al., 1993), whether acute thyroid regulation in the cerebellum affects feeding behavior is currently not known. Further studies of the regulation of Tub by thyroid hormone in other phenotypically relevant sites, such as the hypothalamic nuclei, could lead to important contributions to our understanding of the functional role of TULPs.

	TUB as a mediator in the insulin signaling pathway

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
Kapeller et al. (Kapeller et al., 1999) reported that when the Tub gene was transfected into chinese hamster ovary cells that stably express insulin receptor (CHO-IR), the resultant TUB protein was phosphorylated at tyrosine residues in response to insulin and insulin-like growth factor treatment (Fig. 2a). Furthermore, in vitro studies showed that TUB is directly phosphorylated by the purified insulin receptor kinase, as well as by ABL and JAK2 kinases, but not by the EGF receptor or SRC kinases. The phosphorylated form of TUB appears to bind to the SRC homology 2 (SH2) domains of ABL, LCK and phospholipase C. Therefore, TUB might function as an adapter protein, linking the insulin receptor to SH2-containing proteins. Since the tubby gene is prominently expressed in the brain, this signaling pathway is likely to be active in the neuronal cells in vivo. Interestingly, TUB and the insulin receptors colocalize in neurons of the hypothalamus (Kleyn et al., 1996; He et al., 2000; Unger et al., 1991; Carvalheira et al., 2001), a structure known to be important for regulating energy homeostasis. Recent studies using gene-targeted mice lacking insulin receptor substrate 2 (IRS-2) and brain insulin receptor (INSR) revealed that insulin signaling plays an important role in the energy homeostasis in the brain (Burks et al., 2000; Brüning et al., 2000). It will be interesting to see whether TUB phosphorylation and/or translocation to the nucleus is impaired in the brains of knockout mice in which INSR has been specifically ablated.

	Regulation of TULPs by subcellular localization

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
A distinct functional role of the TULPs may also be conferred by their subcellular localization. In hypothalamic neurons, TUB is localized in the cytoplasm and nucleus (He et al., 2000), whereas in photoreceptor cells it appears to be only in the cytoplasm. In addition, although TUB was only detected in the nucleolus in the hypothalamic neurons, TULP1 was present in structures that are likely to represent the perinucleolar cap and coiled bodies or gems in the nucleus but not the nucleolus (Ikeda et al., 2000). Although it is currently not known why TUB is differentially localized in different cell populations, it is possible that regulatory factors that determine the localization of TUB confer multiple functions upon the TULPs. For example, we found that TUB is localized in the nucleus of the precursor cells of the retinal photoreceptor cells, which undergo proliferation, and TUB localization shifts to the cytoplasm when these cells differentiate (unpublished data).

	Nuclear transport of TUB protein induced by G-protein-coupled receptor signaling

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
TUB is localized in the nucleus as well as in the plasma membrane of cultured cells (Kapeller et al., 1999; Koritschoner et al., 2001; Santagata et al., 2001). Santagata et al. (Santagata et al., 2001) report that TUB is transported from the plasma membrane to the nucleus through G protein _q (G_q) activation (Fig. 2b). Association of TUB with the plasma membrane is thought to occur after its binding to PtdIns(4,5)P₂ (phosphatidylinositol-4,5-bisphosphate), a phospholipid that is highly enriched in the plasma membrane. Release of TUB is triggered by receptor-mediated activation of G_q through the action of phospholipase C-ß. These findings suggest potential candidates for receptors that might regulate TUB in vivo through G_q, such as serotonin (Tecott et al., 1995), bombesin (Ohki-Hamazaki et al., 1997), dopamine D1 (Sidhu, 1998), melanocortin 4 (Huszar et al., 1997) and melanin-concentrating hormone receptors (Chambers et al., 1999; Saito et al., 1999). These receptors are expressed in the hypothalamus and influence feeding behavior and energy homeostasis. Although transfection of serotonin receptor 2c (5HT_2c) induced nuclear translocation of TUB in vitro (Santagata et al., 2001), and a mild obesity phenotype is observed in 5HT_2c null mutant mice (Tecott et al., 1995), other hypothalamic receptors may also play a role in the obesity observed in tubby mice. There is much that still needs to be learned about the regulation of TULPs. Generally, nuclear localization of proteins is regulated by their binding proteins or conformational changes owing to post-translational modification such as phosphorylation. Phosphorylation of TUB may be important for its nuclear localization or, alternatively, additional proteins may be necessary for TUB translocation.

	Mutations in TUB and TULP1 impair rhodopsin transport

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
Extracellular vesicles accumulate near the inner segments of the photoreceptor cells in both Tulp1^–/– and tubby mice (Hagstrom et al., 1999; Ikeda et al., 2000). Hagstrom et al. (Hagstrom et al., 1999) hypothesized that the tubby family normally functions in intracellular vesicular trafficking of opsin and other transported factors (Fig. 2c). Indeed, ectopic localization of rhodopsin is observed (Hagstrom et al., 2001) (A.I., P.M.N. and J.K.N, unpublished) in both Tulp1^–/– and tubby mice. In addition, yeast two-hybrid analysis using TUB as bait identified proteins that are associated with secretory vesicles as binding partners (Hagstrom et al., 2000). These results support a role for TUB and TULP1 in protein trafficking in the photoreceptor cells of the retina.

	Conclusion/Perspectives

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 
Genetic and biochemical studies, which have focused on identifying a common function for the members of the tubby family, have provided insights into potential functions of the TULPs in a wide variety of neuronal cell populations. Continued functional studies aimed at elucidating tissue-specific functions may clarify how TULPs function in cells and how the mutations within these genes cause particular disease pathologies. For example, if TULPs act as transcription factors, do they recognize specific DNA sequences within specific tissues? What kinds of genes are regulated by TULPs? These genes will certainly become key factors in understanding the pathways through which TULPs act. But how can a role as a transcription factor be reconciled with the observed rhodopsin mislocalization and the localization of TUB to the nucleolus? At this point, our current understanding of the function of the tubby-like gene family is reminiscent of the three blind men and the elephant, who after examining different parts of the elephant came to vastly different conclusions about the nature of the beast. Mutants for each tubby family gene studied thus far show significant abnormalities and phenotypes that do not always overlap despite overlapping expression patterns. It is therefore not clear that all of the observed phenotypic characteristics of Tulp mutations can be ascribed to a single pathway with one function. Indeed, it seems possible that TULPS are multifunctional proteins that may play multiple, independent roles in normal cellular function and integrity.

	ACKNOWLEDGMENTS

 
We are grateful to Barbara K. Knowles and Edward H. Leiter for careful review of the manuscript. Research in our laboratory was supported by grants from Foundation for Fighting Blindness, NIH DK59641, and AXYS Pharmaceuticals Inc. Institutional shared services are supported by National Cancer Institute Support grant CA-34196.

	REFERENCES

Top SUMMARY Introduction TULPs are important for... Gene-gene interactions determine... Molecular structure and genetic... Thyroid hormones T3 and... TUB as a mediator... Regulation of TULPs by... Nuclear transport of TUB... Mutations in TUB and... Conclusion/Perspectives REFERENCES

 

Banerjee, P., Kleyn, P. W., Knowls, J. A., Lewis, C. A., Ross, B. M., Parano, E., Kovats, S. G., Lee, J. J., Penchaszadeh, G. K., Ott, J. et al. (1998). TULP1 mutation in two extended Dominican kindreds with autosomal recessive Retinitis pigmentosa. Nat. Genet. 18, 177-179.[Medline]

Boggon, T. J., Shan, W. S., Santagata, S., Myers, S. C. and Shapiro, L. (1999). Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286, 2119-2125.[Abstract/Free Full Text]

Briscoe, J. and Ericson, J. (2001). Specification of neuronal fates in the ventral neural tube. Curr. Opin. Neurobiol. 11, 43-49.[Medline]

Brüning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Muller-Wieland, D. and Kahn, C. R. (2000). Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122-2125.[Abstract/Free Full Text]

Burks, D. J., de Mora, J. F., Schubert, M., Withers, D. J., Myers, M. G., Towery, H. H., Altamuro, S. L, Flint, C. L and White, M. F. (2000). IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377-382.[Medline]

Carvalheira, J. B., Siloto, R. M., Ignacchitt, I., Brenelli, S. L., Carvalho, C. R., Leite, A., Velloso, L. A., Gontijo, J. A. and Saad, M. J. (2001). Insulin modulates leptin-induced STAT3 activation in rat hypothalamus. FEBS Lett. 500, 119-124.[Medline]

Chambers, J., Ames, R. S., Bergsma, D., Muir, A., Fitzgerald, L. R., Hervieu, G., Dytko, G. M., Foley, J. J., Martin, J., Liu, W. S. et al. (1999). Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 400, 261-265.[Medline]

Coleman, D. L. and Eicher, E. M. (1990). Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J. Hered. 81, 424-427.[Abstract/Free Full Text]

Forrest, D., Erway, L. C., Ng, L., Altschuler, R. and Curran, T. (1996). Thyroid hormone receptor beta is essential for development of auditory function. Nat. Genet. 13, 354-357.[Medline]

Gibson, T. J. and Spring, J. (2000). Evolution of sequences, structures, and genomes. Biochem. Soc. Trans. 28, 259-264.[Medline]

Guan, X. M., Yu, H. and Van der Ploeg, L. H. (1998). Evidence of altered hypothalamic pro-opiomelanocortin/neuropeptide Y mRNA expression in tubby mice. Brain Res. Mol. Brain Res. 59, 273-279.[Medline]

Hagstrom, S. A., North, M., Nishina, P. M., Berson, E. and Dryja, T. (1998). Recessive mutations in the gene encoding the tubby-like protein, TULP1, in patients with retinitis pigmentosa. Nat. Genet. 18, 174-176.[Medline]

Hagstrom, S. A., Duyao, M., North, M. A. and Li, T. (1999). Retinal degeneration in tulp1–/– mice: vesicular accumulation in the interphotoreceptor matrix. Invest. Ophthalmol. Vis. Sci. 40, 2795-2802.[Abstract/Free Full Text]

Hagstrom, S. H., Yue, G., Scimeca, M. and Li, T. (2000). Search for TULP1 function by analyzing animal models and by screening for interacting proteins. Invest. Ophthalmol. Vis. Sci. 41, S532 (Abstract 2833).

Hagstrom, S. A., Adamian, M., Scimeca, M., Pawlyk, B. S., Yue, G. and Li, T. (2001). A role for the Tubby-like protein 1 in rhodopsin transport. Invest. Ophthalmol. Vis. Sci. 42, 1955-1962.[Abstract/Free Full Text]

He, W., Ikeda, S., Bronson, R. T., Yan, G., Nishina, P. M., North, M. A. and Naggert, J. K. (2000). GFP-tagged expression and immunohistochemical studies to determine the subcellular localization of the tubby gene family members. Mo. Brain Res. 81, 109-117.

Heckenlively, J. R., Chang, B., Erway, L. C., Peng, C., Hawes, N. L., Hageman, G. S. and Roderick, T. H. (1995). Mouse model for Usher syndrome: Linkage mapping suggests homology to Usher type I reported at human chromosome 11p15. Proc. Natl. Acad. Sci. 92, 11100-11104.[Abstract/Free Full Text]

Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D. et al. (1997). Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141.[Medline]

Ikeda, A., Zheng, Q. Y., Rosenstiel, P., Maddatu, T., Zuberi, A. R., Roopenian, D. C., North, M. A., Naggert, J. K., Johnson, K. R. and Nishina, P. M. (1999a). Genetic modification of hearing in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss. Hum. Mol. Genet. 8, 1761-1767.[Abstract/Free Full Text]

Ikeda, A., Ikeda, S., Gridley, T., Nishina, P. M. and Naggert, J. K. (2001). Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice. Hum. Mol. Genet. 10, 1325-1334.[Abstract/Free Full Text]

Ikeda, S., He, W., Ikeda, A., Naggert, J. K., North, M. A. and Nishina, P. M. (1999b). Cell specific expression of tubby gene family members in the retina. Invest. Ophthalmol. Vis. Sci. 40, 2706-2712.[Abstract/Free Full Text]

Ikeda, S., Shiva, N., Ikeda, A., Smith, R. S., Nusinowitz, S., Yan, G., Lin, T. R., Chu, S., Heckenlively, J. R., North, M. A. et al. (2000). Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. Hum. Mol. Genet. 22, 155-163.

Kapeller, R., Moriarty, A., Strauss, A., Stubdal, H., Theriault, K., Siebert, E., Chickering, T., Morgenstern, J. P., Tartaglia, L. A. and Lillie, J. (1999). Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin. J. Biol. Chem. 274, 24980-24986.[Abstract/Free Full Text]

Kleyn, P. W., Fan, W., Kovats, S. G., Lee, J. J., Pulido, J. C., Wu, Y., Berkemeier, L. R., Misumi, D. J., Holmgren, L., Charlat, O. et al. (1996). Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85, 281-290.[Medline]

Koritschoner, N. P., Alvarez-Dolado, M., Kurz, S. M., Heikenwalder, M. F., Hacker, C., Vogel, F., Munoz, A. and Zenke, M. (2001). Thyroid hormone regulates the obesity gene tub. EMBO Rep. 2, 499-504.[Medline]

Krotkiewski, M. (2000). Thyroid hormones and treatment of obesity. Int. J. Obes. Relat. Metab. Disord. 24, S116-S119.

Lucchi, M. L., Callegari, E., Barazzoni, A. M., Chiocchetti, R., Clavenzani, P. and Bortolami, R. (1998). Cerebellar and spinal projections of the coeruleus complex in the duck: a fluorescent retrograde double-labeling study. Anat. Rec. 251, 392-397.[Medline]

Lewis, C. A., Batlle, I. R., Batlle, K. G., Banerjee, P., Cideciyan, A. V., Huang, J., Aleman, T. S., Huang, Y., Ott, J., Gilliam, T. C. et al. (1999). Tubby-like protein 1 homozygous splice-site mutation causes early-onset severe retinal degeneration. Invest. Ophthalmol. Vis. Sci. 40, 2106-2114.[Abstract/Free Full Text]

Mahler, P., Guastavino, J. M., Jacquart, G. and Strazielle, C. (1993). An unexpected role of the cerebellum: involvement in nutritional organization. Physiol. Behav. 54, 1063-1067.[Medline]

Marszalek, J. R., Liu, X., Roberts, E. A., Chui, D., Marth, J. D., Williams, D. S. and Goldstein, L. S. (2000). Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102, 175-187.[Medline]

Morimoto, A., Suzumi, M., Sakata, Y. and Murakami, N. (1984). Activation of brain regions in rats during food-intake operant behavior. Physiol. Behav. 33, 965-968.[Medline]

Ng, L., Hurley, J. B., Dierks, B., Srinivas, M., Salto, C., Vennstrom, B., Reh, T. A. and Forrest, D. (2001). A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nat. Genet. 27, 94-98.[Medline]

Nishina, P. M., North, M. A., Ikeda, A., Yan, Y. and Naggert, J. K. (1998). Molecular characterization of a novel tubby gene family member, TULP3, in mouse and human. Genomics 54, 215-220.[Medline]

Nishina, P. M., Ikeda, A. and Naggert, J. K. (2000). Identification of QTLs for protection from photoreceptor cell degeneration in tubby mice. Invest. Ophthalmol. Vis. Sci. 41, S202 (Abstract 1057).

Noben-Trauth, K., Naggert, J. K., North, M. A. and Nishina, P. M. (1996). A candidate gene for the mouse mutation tubby. Nature 380, 534-538.[Medline]

North, M. A., Naggert, J. K., Yan, Y., Noben-Trauth, K. and Nishina, P. M. (1997). Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc. Natl. Acad. Sci. 94, 3128-3133.[Abstract/Free Full Text]

Ohki-Hamazaki, H., Watase, K., Yamamoto, K., Ogura, H., Yamano, M., Yamada, K., Maeno, H., Imaki, J., Kikuyama, S., Wada, E. and Wada, K. (1997). Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity. Nature 390, 165-169.[Medline]

Ohlemiller, K. K., Hughes, R. M., Lett, J. M., Ogilvie, J. M., Speck, J. D., Wright, J. S. and Faddis, B. T. (1997). Progression of cochlear and retinal degeneration in the tubby (rd5) mouse. Audiol. Neuro-Otol. 2, 175-185.[Medline]

Paloma, E., Hjelmqvist, L., Bayes, M., Garcia-Sandoval, B., Ayuso, C., Balcells, S. and Gonzalez-Duarte, R. (2000). Novel mutations in the TULP1 gene causing autosomal recessive retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 41, 656-659.[Abstract/Free Full Text]

Saito, Y., Nothacker, H. P., Wang, Z., Lin, S. H., Leslie, F. and Civelli, O. (1999). Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400, 265-269.[Medline]

Sahly, I., Gogat, K., Kobetz, A., Marchant, D., Menasche, M., Castel, M., Revah, F., Dufier, J., Guerre-Millo, M. and Abitbol, M. M. (1998). Prominent neuronal-specific tub gene expression in cellular targets of tubby mice mutation. Hum. Mol. Genet. 7, 1437-1447.[Abstract/Free Full Text]

Santagata, S., Boggon, T. J., Baird, C. L., Gomez, C. A., Zhao, J., Shan, W. S., Myszka, D. G. and Shapiro, L. (2001). G-protein signaling through tubby proteins. Science 292, 2041-2050.[Abstract/Free Full Text]

Sidhu, A. (1998). Coupling of D1 and D5 dopamine receptors to multiple G proteins: Implications for understanding the diversity in receptor-G protein coupling. Mol. Neurobiol. 16, 125-134.[Medline]

Stubdal, H., Lynch, C. A., Moriarty, A., Fang, Q., Chickering, T., Deeds, J. D., Fairchild-Huntress, V., Charlat, O., Dunmore, J. H., Kleyn, P. et al. (2000). Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation. Mol. Cell Biol. 20, 878-882.[Abstract/Free Full Text]

Tai, A. W., Chuang, J. Z., Bode, C., Wolfrum, U. and Sung, C. H. (1999). Rhodopsin’s carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell 97, 877-887.[Medline]

Tecott, L. H., Sun, L. M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F. and Julius, D. (1995). Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374, 542-546.[Medline]

Troutt, L. L. and Burnside, B. (1988). Microtubule polarity and distribution in teleost photoreceptors. J. Neurosci. 8, 2371-2380.[Abstract]

Unger, J. W., Livingston, J. N. and Moss, A. M. (1991). Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog. Neurobiol. 36, 343-362.[Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				V. L. Patterson, C. Damrau, A. Paudyal, B. Reeve, D. T. Grimes, M. E. Stewart, D. J. Williams, P. Siggers, A. Greenfield, and J. N. Murdoch Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway Hum. Mol. Genet., May 15, 2009; 18(10): 1719 - 1739. [Abstract] [Full Text] [PDF]

				R. X. Norman, H. W. Ko, V. Huang, C. M. Eun, L. L. Abler, Z. Zhang, X. Sun, and J. T. Eggenschwiler Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling Hum. Mol. Genet., May 15, 2009; 18(10): 1740 - 1754. [Abstract] [Full Text] [PDF]

				Y. Yamaguchi, T. Passeron, T. Hoashi, H. Watabe, F. Rouzaud, K.-i. Yasumoto, T. Hara, C. Tohyama, I. Katayama, T. Miki, et al. Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/{beta}-catenin signaling in keratinocytes FASEB J, April 1, 2008; 22(4): 1009 - 1020. [Abstract] [Full Text] [PDF]

				X. Yi, M. Schubert, N. S. Peachey, K. Suzuma, D. J. Burks, J. A. Kushner, I. Suzuma, C. Cahill, C. L. Flint, M. A. Dow, et al. Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells J. Neurosci., February 2, 2005; 25(5): 1240 - 1248. [Abstract] [Full Text] [PDF]

				D. P. Figlewicz, A. Zavosh, T. Sexton, and J. F. Neumaier Catabolic action of insulin in rat arcuate nucleus is not enhanced by exogenous "tub" expression Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E1004 - E1010. [Abstract] [Full Text] [PDF]

				D. A. William, Y. Su, M. R. Smith, M. Lu, D. A. Baldwin, and D. Wagner Genomic identification of direct target genes of LEAFY PNAS, February 10, 2004; 101(6): 1775 - 1780. [Abstract] [Full Text] [PDF]

				J. P. DiNitto, T. C. Cronin, and D. G. Lambright Membrane Recognition and Targeting by Lipid-Binding Domains Sci. Signal., December 16, 2003; 2003(213): re16 - re16. [Abstract] [Full Text] [PDF]

				D W Hommes, M P Peppelenbosch, and S J H van Deventer Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets Gut, January 1, 2003; 52(1): 144 - 151. [Abstract] [Full Text] [PDF]

This Article Summary Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ikeda, A. Articles by Naggert, J. K. Search for Related Content PubMed PubMed Citation Articles by Ikeda, A. Articles by Naggert, J. K. Social Bookmarking                         What's this?