Teneurins are type II transmembrane proteins expressed during pattern formation and neurogenesis with an intracellular domain that can be transported to the nucleus and an extracellular domain that can be shed into the extracellular milieu. In Drosophila melanogaster, Caenorhabditis elegans, and mouse the knockdown or knockout of teneurin expression can lead to abnormal patterning, defasciculation, and abnormal pathfinding of neurites, and the disruption of basement membranes. Here, we have identified and analyzed teneurins from a broad range of metazoan genomes for nuclear localization sequences, protein interaction domains, and furin cleavage sites and have cloned and sequenced the intracellular domains of human and avian teneurins to analyze alternative splicing. The basic organization of teneurins is highly conserved in Bilateria: all teneurins have epidermal growth factor (EGF) repeats, a cysteine-rich domain, and a large region identical in organization to the carboxy-half of prokaryotic YD-repeat proteins. Teneurins were not found in the genomes of sponges, cnidarians, or placozoa, but the choanoflagellate Monosiga brevicollis has a gene encoding a predicted teneurin with a transmembrane domain, EGF repeats, a cysteine-rich domain, and a region homologous to YD-repeat proteins. Further examination revealed that most of the extracellular domain of the M. brevicollis teneurin is encoded on a single huge 6,829-bp exon and that the cysteine-rich domain is similar to sequences found in an enzyme expressed by the diatom Phaeodactylum tricornutum. This leads us to suggest that teneurins are complex hybrid fusion proteins that evolved in a choanoflagellate via horizontal gene transfer from both a prokaryotic gene and a diatom or algal gene, perhaps to improve the capacity of the choanoflagellate to bind to its prokaryotic prey. As choanoflagellates are considered to be the closest living relatives of animals, the expression of a primitive teneurin by an ancestral choanoflagellate may have facilitated the evolution of multicellularity and complex histogenesis in metazoa.

In the developing pancreas, the basic helix-loop-helix (bHLH) protein Neurogenin3 (Ngn3) specifies which precursor cells ultimately will become endocrine cells and initiates the islet differentiation program. NeuroD1, a closely related bHLH protein and a downstream target of Ngn3, maintains the differentiation program initiated by Ngn3. We have developed an in vitro model of Ngn3-dependent differentiation by infecting pancreatic duct cell lines with an Ngn3-expressing adenovirus. We found that both Ngn3 and its downstream target NeuroD1 activated the islet differentiation program in these cells by inducing the expression of genes with early roles in the differentiation cascade, as well as genes characteristic of fully differentiated islet cells. Induction of these genes, as exemplified by the insulin1 gene, involved alteration of the local chromatin structure. Interestingly, the subsets of genes activated by Ngn3 and NeuroD1 were not completely overlapping, indicating that these two bHLH proteins serve specific functions in the development of the endocrine pancreas. In addition, microarray gene expression analysis identified a previously uncharacterized group of Ngn3-induced genes with potentially important roles in islet development and function. These studies demonstrate how Ngn3 initiates islet differentiation and provide us with a model for testing methods for producing islet cells for people with diabetes. During pancreatic development, differentiation of endocrine and exocrine cells from a common endodermal progenitor cell requires the coordinated regulation of specific sets of genes. This process can be envisioned as a hierarchy or cascade of transcription factors that initiate and maintain the distinct gene expression programs that define the various pancreatic cell types (1). Among these factors, the basic helix-loop-helix (bHLH) protein Neurogenin3 (Ngn3) plays a dominant role in the specification of the endocrine͞islet cell lineage.During embryonic development, Ngn3 appears transiently in scattered pancreatic epithelial cells (2, 3). Several lines of evidence indicate that the expression of Ngn3 in these undifferentiated cells directs them to an endocrine cell fate and initiates the program of islet differentiation. First, lineage tracing shows that these transient Ngn3-expressing cells differentiate exclusively into islet cells (4). Second, mice homozygous for a targeted deletion of the ngn3 gene fail to generate any islet cells (5). Third, ectopic expression of Ngn3 drives embryonic endoderm to an endocrine fate (2, 3, 6).Ngn3 may play a similar role in the generation of new islet cells postnatally. It has been suggested that cells along the pancreatic ducts may act as progenitors for new islet cells in the postnatal period, although recent lineage tracing experiments suggest that the bulk of newly generated beta cells in adult mice result from the replication of preexisting beta cells (7).Ngn3 initiates islet cell differentiation, but other factors downstream of ngn3 must complete the task. Genetic...

Background: Teneurins are a unique family of transmembrane proteins conserved from C. elegans and D. melanogaster to mammals. In vertebrates there are four paralogs (teneurin-1 to -4), all of which are expressed prominently in the developing central nervous system.

ATAD2 is an E2F target gene that is highly expressed in gastrointestinal and breast carcinomas. Here we characterize a related gene product, ATAD2B. Both genes are evolutionarily conserved, with orthologues present in all eukaryotic genomes examined. Human ATAD2B shows a high degree of similarity to ATAD2. Both contain an AAA domain and a bromodomain with amino acid sequences sharing 97% and 74% identity, respectively. The expression of ATAD2B was studied in the chicken embryo using a polyclonal antibody raised against a recombinant fragment of human ATAD2B. Immunohistochemistry revealed transient nuclear expression in subpopulations of developing neurons. The transient nature of the expression was confirmed by immunoblotting homogenates of the developing telencephalon. Cell fractionation was used to confirm the nuclear localization of ATAD2B in the developing nervous system: anti-ATAD2B recognizes a smaller band (approximately 160 kDa) in the nuclear fraction and a larger band (approximately 300 kDa) in the membrane fraction, suggesting that posttranslational processing of ATAD2B may regulate its transport to the nucleus. The expression of ATAD2B was also studied in human tumors. Oncomine and immunohistochemistry reveal ATAD2B expression in glioblastoma and oligodendroglioma; ATAD2B immunostaining was also elevated in human breast carcinoma. In tumors ATAD2B appears to be cytoplasmic or membrane bound, and not nuclear. Our observations suggest that ATAD2B may play a role in neuronal differentiation and tumor progression.