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PubMed2000

Combinatorial expression of zebrafish Brn-1- and Brn-2-related POU genes in the embryonic brain, pronephric primordium, and pharyngeal arches.

Vertebrate class III POU genes are widely expressed in the embryonic and adult central nervous system, where they act as transcriptional regulators of cell- and/or region-specific gene expression. We isolated four zebrafish class III POU genes, named zp-12, zp-23, zp-47 and zp-50. In this study, we examined the developmental expression patterns of the Brn-1- and Brn-2-related zp-12, zp-23 and zp-47 genes by means of whole-mount in situ hybridization. Similarly to their mammalian orthologues, the major expression site of all zebrafish zp genes is the CNS. Neurectodermal expression was first detected at the beginning of somitogenesis in spatially restricted segment-like domains in different parts of the neural plate. During somitogenesis transcript distributions changed from highly restricted to widespread but nevertheless distinct patterns found in all major subdivisions of the CNS. While zp-47 expression was detected exclusively in the CNS, localized expression of zp-12 and zp-23 was also found in the pronephric primordium and in cell clusters within the mandibular and hyoid arches. Furthermore, zp-23 transcripts were transiently detected in a restricted region of the paraxial mesendoderm and, at late embryogenesis stages, in the auditory vesicles. The early regionalized expression of all three zp genes is compatible with roles in regional specification of the neural plate. Comparison of the distinct yet overlapping expression of zp-12, zp-23, zp-47 and the previously characterized zp-50 gene implies both unique, as well as redundant functions for each family member. We propose that coordinate expression of particular combinations of class III POU genes contribute to pattern formation or cell fate determination in the developing CNS and other structures.

Animals↗
PubMed1996

Oct-6 (SCIP/Tst-1) is expressed in Schwann cell precursors, embryonic Schwann cells, and postnatal myelinating Schwann cells: comparison with Oct-1, Krox-20, and Pax-3.

The POU domain transcription factor Oct-6 (SCIP/Tst-1) is likely to control important stages of Schwann cell development, including the initiation of myelination around birth. Here, we use immunocytochemical and reverse transcriptase-polymerase chain reaction techniques to examine Oct-6 earlier in nerve development, to test the idea that Oct-6 has an additional role in Schwann cell precursors or early embryonic Schwann cells, a possibility raised by previous studies on transgenic mice. Consistent with this, we find low but unambiguous levels of Oct-6 mRNA and protein in Schwann cell precursors of mouse and rat (nerves from 12- and 14-day-old embryos, respectively), with expression levels gradually increasing during early Schwann cell development and towards birth. Unexpectedly, Oct-6 immunoreactivity is clearly present in nuclei of most myelinating cells at least as late as postnatal day 12. Furthermore, many nonmyelinating Schwann cells express Oct-6 in adult life. A comparison of Oct-6 mRNA with other Schwann cell transcription factors-namely, Oct-1, Krox-20, and Pax-3-reveals that each factor exhibits strong developmental regulation and a unique expression pattern in embryonic nerves. Therefore, they are likely to play distinct regulatory roles in early development of the Schwann cell lineage.

Animals↗
PubMed1998

Placodal origin of Brn-3-expressing cranial sensory neurons.

The Brn-3 class of POU-domain transcription factors includes three genes in mammals which have key roles in the development of specific groups of sensory neurons. Here, we have identified three avian genes which correspond to the murine genes Brn-3.0, Brn-3.1, and Brn-3.2. Using an in situ hybridization probe generic for this gene class, the earliest detectable expression of Brn-3 in the chick is at stage 15, in placodal and migrating precursors of the trigeminal ganglion. By stage 19, Brn-3.0 protein is detectable in the trigeminal and vestibulocochlear ganglia with Brn-3.0-specific antisera, and Brn-3 message expression has extended to the dorsal root ganglia. At later stages, when condensation of the trigeminal ganglion is complete, Brn-3.0-immunoreactive neurons are concentrated in the portion of the ganglion distal to the brain stem. To examine the developmental origin of the Brn-3 expressing cells, we combined lipophilic dye (DiI) labeling with in situ hybridization. DiI labeling of the placodal surface ectoderm and of premigratory neural crest cells in the neural tube reveals that all, or nearly all, of the Brn3-expressing neurons in the trigeminal ganglia are derived from the sensory placodes and not from the neural crest, and thus, that Brn-3 is an early marker of the placode-derived sensory neural lineage.

Amino Acid Sequence↗
PubMed1997

The molecular basis of X-linked deafness type 3 (DFN3) in two sporadic cases: identification of a somatic mosaicism for a POU3F4 missense mutation.

We have investigated two unrelated males with X-linked deafness type 3 (DFN3) for mutations in the POU3F4 gene. In one patient, we observed a mutation that is predicted to result in an Arg330Ser amino acid substitution. In another DFN3 patient, a somatic mosaicism for an Arg323Gly amino acid substitution was found. This mosaicism was detected in two independently established EBV immortalized B cells and peripheral blood lymphocytes (PBLs). Semiquantitative analysis showed that approximately 50% of the PBLs of this patient carry the mutation. We hypothesize that the Arg323Gly mutation occurred very early in embryogenesis, before the differentiation of cells involved in hematopoiesis and inner ear development. In both patients, the missense mutations are situated in the POU homeodomain and are predicted to disrupt the DNA binding of the POU3F4 protein. All nine point mutations thus far described were found in the POU domains of POU3F4. Since these domains constitute only 35% of the open reading frame of POU3F4, there is a statistically significant preference for mutations in the POU-specific and POU homeodomain.

Adult↗
PubMed2006

Expression of qBrn-1, a new member of the POU gene family, in the early developing nervous system and embryonic kidney.

It has been shown that POU domain genes play critical roles in the development of the nervous system. We have obtained a new member of the class III POU domain genes, qBrn-1, from the cDNA library of embryonic day 5 quail and have made an extensive expression pattern analysis of qBrn-1 and qBrn-2 throughout the early embryonic development by in situ hybridization. With a specific antibody we prepared, further analysis by immunohistochemistry showed that the location of qBrn-1 protein was consistent with that of the transcripts in the early developing quail. Our results showed that both qBrn-1 and qBrn-2 were preferentially expressed in the developing central nervous system, and their transcripts were initially detected in the neural plate and later in the distinct regions of the neural tube with a stage-dependent pattern. Moreover, their expression was also detected in both notochord and neural crests. However, qBrn-1 signal, different from qBrn-2, was more widely found in the auditory pits, branchial arches, and in the mesodermal components of the developing kidney. And the expression of qBrn-1 in nephric region was earlier and wider than that of mouse Brn-1, suggesting the characteristic function of qBrn-1 in the kidney formation. The distinct dynamic expression patterns of qBrn-1 and qBrn-2 indicate multiple roles of the class III POU genes in quail neurogenesis and organogenesis.

Amino Acid Sequence↗
PubMed1992

A fungal mating type protein that regulates sexual and asexual development contains a POU-related domain.

The A mating type factor of the fungus Coprinus cinereus regulates essential steps in sexual development. Here we describe features of one of the four specificity genes of the A42 factor. By transformation we show that the gene regulates not only sexual development but also asexual sporulation. DNA sequence analysis shows that the gene beta 1-1, encodes a protein with a DNA binding motif and is thus likely to be a transcription factor. The DNA binding domain is an unusual homeodomain with D replacing the normally invariant N in the recognition helix and apparent absence of helix II. The homeodomain is linked to a helical region related to the POUs domain, which is part of a bipartite DNA binding domain of certain animal transcription factors. Like POU factors, the beta 1-1 protein has regions rich in serine, threonine and proline which are possible transactivation domains. Putative dimerization domains and sites for post-translational modification are described.

Amino Acid Sequence↗
PubMed1998

GENFOLD: a genetic algorithm for folding protein structures using NMR restraints.

We report the development and validation of the program GENFOLD, a genetic algorithm that calculates protein structures using restraints obtained from NMR, such as distances derived from nuclear Overhauser effects, and dihedral angles derived from coupling constants. The program has been tested on three proteins: the POU domain (a small three-helix DNA-binding protein), bovine pancreatic trypsin inhibitor (BPTI), and the starch-binding domain from Aspergillus niger glucoamylase I, a 108-residue beta-sheet protein. Structures were calculated for each protein using published NMR restraints. In addition, structures were calculated for BPTI using artificial restraints generated from a high-resolution crystal structure. In all cases the fittest calculated structures were close to the target structure, and could be refined to structures indistinguishable from the target structures by means of a low-temperature simulated annealing refinement. The effectiveness of the program is similar to that of distance geometry and simulated annealing methods, and it is capable of using a very wide range of restraints as input. It can thus be readily extended to the calculation of structures of large proteins, for which few NOE restraints may be available.

Algorithms↗
PubMed1995

Early embryonic expression of XLPOU-60, a Xenopus POU-domain protein.

XLPOU-60 is a Xenopus POU-domain gene whose expression is tightly controlled during early development at transcriptional, post-transcriptional, translational, and post-translational levels. We report the expression pattern of the XLPOU-60 protein; it is first detectable in the stage V oocyte and accumulates rapidly following fertilisation, reaching a peak at the time of the mid-blastula transition. In the blastula, XLPOU-60 protein translated from injected synthetic mRNA enters nuclei. During gastrulation, both transcript and protein are rapidly down-regulated in a cell-autonomous manner; down-regulation is not dependent on cell-cell contact or induction by activin in an animal cap assay. For the mRNA, this down-regulation correlates with changes in the length of its poly(A) tail and is dependent on sequences in the untranslated regions of the transcript. On the basis of its protein expression pattern and known DNA-binding properties, we speculate that XLPOU-60 may play a role in the control of early transcriptional events in the Xenopus embryo.

Animals↗
PubMed1995

The Ames dwarf gene is required for Pit-1 gene activation.

The tissue-specific POU domain transcription factor Pit-1 is required for phenotypic specification of three cell types in the anterior pituitary gland of mammals: somatotropes, thyrotropes, and lactotropes. Mutations in the Pit-1 gene, as first described in Snell and Jackson dwarf (dw) mice, led to pituitary hypoplasia due to lack of these three cell types, as well as hypothyroidism and dwarfism because of deficiency of thyroid-stimulating hormone and growth hormone, respectively. The Ames dwarf (df) exhibits a phenotype identical to that of Pit-1 mutated mice but the defective gene has been mapped to a locus on mouse chromosome 11, distinct from the Pit-1 gene located on mouse chromosome 6. Our studies indicate that initial activation of the Pit-1 gene is deficient in the Ames dwarf. This suggests that the df gene is required for activation of the Pit-1 gene and provides evidence for a hierarchy of tissue-specific factors required for cellular commitment in the anterior pituitary gland.

Animals↗
PubMed1997

Inhibitory effects of ventral signals on the development of Brn-3.0-expressing neurons in the dorsal spinal cord.

Brn-3.0, a POU-domain transcription factor, is expressed in specific postmitotic neurons in the dorsal part of the neural tube which are among the first spinal cord neurons to appear in development. In the mature spinal cord, the Brn-3.0 cells form a numerous population of scattered neurons in the intermediate spinal gray. Ablation of the notochord in chick embryos extends the domain of Brn-3.0 expression into the ventral neural tube, while ectopic grafts of notochord tissue suppress Brn-3.0 expression. The notochord effects on Brn-3.0 expression are reproduced in vivo by the implantation of a local source of recombinant Shh protein. The down-regulation of Brn-3.0 expression in the dorsal spinal cord by the notochord and Shh contrasts with the known inductive effects of these ventral signals on the approximately simultaneous development of the spinal motor neurons. In cultured explants of neural plate from the region of the presumptive spinal cord, Brn-3.0 neurons develop in the absence of surface ectoderm and ventral midline tissue, suggesting that the Brn-3.0 phenotype may represent a "default" developmental pathway for early spinal cord neurons. Together these results advance the understanding of the mechanism of the generation of neuronal diversity in the developing vertebrate CNS.

Animals↗
PubMed1998

Requirement for Brn-3b in early differentiation of postmitotic retinal ganglion cell precursors.

The Brn-3 subfamily of POU domain transcription factors consists of Brn-3a, -3b, and -3c, which are important regulators for sensorineural development. Despite the expression of all three factors in retinal ganglion cells, earlier studies have shown that Brn-3b is the only one among the three Brn-3 genes that is essential for development of approximately 70% of ganglion cells in the murine retina. I report here that Brn-3b displays a spatiotemporal expression pattern characteristic of the dynamic profile of ganglion cell genesis during murine retinal development. Moreover, it is initially turned on in postmitotic ganglion cell precursors 2 days before the onset of Brn-3a and -3c expression in differentiated ganglion cells. During the entire period of retinal ganglion cell genesis, the postmitotic ganglion cell precursors that would normally become Brn-3b+ cells fail to properly differentiate in Brn-3b-/- mice, as evidenced by a twofold reduction in the optic nerve size and diminished expression of several ganglion cell markers. The undifferentiated ganglion cell precursors appear to be degenerated by apoptosis within the ganglion cell layer during the perinatal and early postnatal period. I propose that retinal ganglion cells develop following two separate differentiation pathways--Brn-3b dependent and Brn-3b independent. In the Brn-3b-dependent mechanism, Brn-3b may be required to initiate a particular differentiation program for a large set of postmitotic ganglion precursors to properly differentiate into the 70%, Brn-3b-dependent retinal ganglion cells.

Animals↗
PubMed2001

Brn-3a activates the expression of Bcl-x(L) and promotes neuronal survival in vivo as well as in vitro.

The determination of cell fate plays a critical role during the later stages of embryogenesis and the early postnatal period-a time during which approximately half of neurons born during neurogenesis undergo programmed cell death. It has previously been reported that the type IV POU domain transcription factor Brn-3a plays a role in the maturation and survival of sensory neuronal populations. Indeed we have shown that the long form of Brn-3a is capable of activating expression of the antiapoptotic Bcl-2 gene and enhancing neuronal survival in cultures of sensory neurons. In this study, we report the identification of another antiapoptotic family member, Bcl-x(L), as a target gene of Brn-3a in sensory neurons, providing a further mechanism by which Brn-3a determines sensory neuronal fate during development. Bcl-x(L) gene expression is activated by Brn-3a in sensory but not in sympathetic neurons and its expression is reduced by antisense inhibition of Brn-3a expression in sensory neurons. Most importantly, both Bcl-x(L) expression and neuronal survival are enhanced by the overexpression of Brn-3a in dorsal root ganglion in vivo in a model of sciatic nerve injury in the intact animal.

Animals↗
PubMed2001

The wings of Bombyx mori develop from larval discs exhibiting an early differentiated state: a preliminary report.

Lepidopteran insects present a complex organization of appendages which develop by various mechanisms. In the mulberry silkworm, Bombyx mori a pair of meso- and meta-thoracic discs located on either side in the larvae gives rise to the corresponding fore- and hind-wings of the adult. These discs do not experience massive cell rearrangements during metamorphosis and display the adult wing vein pattern. We have analysed wing development in B. mori by two approaches, viz., expression of patterning genes in larval wing discs, and regulatory capacities of larval discs following explantation or perturbation. Expression of Nubbin is seen all over the presumptive wing blade domains unlike in Drosophila, where it is confined to the hinge and the wing pouch. Excision of meso- and meta-thoracic discs during the larval stages resulted in emergence of adult moths lacking the corresponding wings without any loss of thoracic tissues suggesting independent origin of wing and thoracic primordia. The expression of wingless and distal-less along the dorsal/ventral margin in wing discs correlated well with their expression profile in adult Drosophila wings. Partially excised wing discs did not show in situ regeneration or duplication suggesting their early differentiation. The presence of adult wing vein patterns discernible in larval wing discs and the patterns of marker gene expression as well as the inability of these discs to regulate growth suggested that wing differentiation is achieved early in B. mori. The timings of morphogenetic events are different and the wing discs behave like presumptive wing buds opening out as wing blades in B. mori unlike evagination of only the pouch region as wing blades seen in Drosophila.

Animals↗
PubMed2002

Embryonic development in the primitive bilaterian Neochildia fusca: normal morphogenesis and isolation of POU genes Brn-1 and Brn-3.

Neochildia fusca is a member of the taxon Acoela, a group of flatworms that, according to some recent molecular phylogenetic analyses, are distinct from other flatworms and constitute a basal branch with a sister taxon relationship to the rest of the Bilateria. In this paper, we analyze early neural development in this species and report the sequence and expression of two Pit-Oct-Unc (POU) genes, NeocBrn-1 and NeocBrn-3. Homologs of these highly conserved genes play a role in neural fate determination in vertebrates, Drosophila and Caenorhabditis elegans. Acoels, including Neochildia, have a unique invariant pattern of early cleavage called duet spiral cleavage. In subsequent cell divisions descendants of the first three micromere duets form an outer layer of epidermal and neural progenitors surrounding the meso/endoderm progenitors, which are themselves descended from the macromere duet 4A, B and the micromere duet 4a, b. Organ formation begins at mid-embryonic stages with the epidermal primordium adopting a ciliated epithelial shape. Sub-epidermally, a bilaterally symmetric brain primordium can be seen at the anterior pole. Laterally and posteriorly, myoblasts form a thin layer underneath the epidermis. In late embryos and juveniles of Neochildia, the brain is formed by a 3-4 cell-diameter-thick layer of neurons forming a cortex surrounding a neuropile that is relatively free of cell bodies. A highly regular "orthogonal" array of muscle fibers penetrates the brain. We have isolated and partially sequenced homologs of the vertebrate Brn-1 and Brn-3 genes, which we call NeocBrn-1 and NeocBrn-3, respectively. These sequences contain and span portions of the POU-specific domain and a homeodomain, and are sequence similar to their respective homologs in vertebrates and Drosophila. RT-PCR reveals that NeocBrn-1 and NeocBrn-3 are expressed from mid-embryonic to adult stages. Whole-mount in situ hybridization shows expression of both genes in distinct subsets of nerve cells in juvenile and adult worms. NeocBrn-1 also appears in a subset of intra-epidermal gland cells. These observations are an initial step towards reconstructing the neural development of a key group of bilaterians, the Acoela. These flatworms, by virtue of their distinct morphology, development and phylogenetically basal placement, are likely to provide key insights into the interpretation of the evolution of metazoan neural architecture.

Amino Acid Sequence↗
PubMed2006

Age-related changes in cochlear gene expression in normal and shaker 2 mice.

The vertebrate cochlea is a complex organ optimized for sound transduction. Auditory hair cells, with their precisely arranged stereocilia bundles, transduce sound waves to electrical signals that are transmitted to the brain. Mutations in the unconventional myosin XV cause deafness in both human DFNB3 families and in shaker 2 (sh2) mice as a result of defects in stereocilia. In these mutant mice, hair cells have relatively normal spatial organization of stereocilia bundles but lack the graded, stair-step organization. We used sh2 mice as an experimental model to investigate the molecular consequences of the sh2 mutation in the Myo15 gene. Gene expression profiling with Affymetrix GeneChips in deaf homozygous (sh2/sh2) mice at 3 weeks and 3 months of age, and in age-matched, normal-hearing heterozygotes (+/sh2) identified only a few genes whose expression was affected by genotype, but a large number with age-associated changes in expression in both normal mice and sh2/sh2 homozygotes. Microarray data analyzed using Robust Multiarray Average identified Aim1, Dbi, and Tm4sf3 as genes with increased expression in sh2/sh2 homozygotes. These increases were confirmed by quantitative reverse transcription-polymerase chain reaction. Genes exhibiting altered expression with age encoded collagens and proteins involved in collagen maturation, extracellular matrix, and bone mineralization. These results identified potential cellular pathways associated with myosin XV defects, and age-associated molecular events that are likely to be involved in maturation of the cochlea and auditory function.

Aging↗
PubMed1992

A POU-domain gene of zebrafish, ZFPOU1, specifically expressed in the developing neural tissues.

We have isolated a POU domain-containing cDNA (ZFPOU1) from a cDNA library of zebrafish (Brachydanio rerio). The ZFPOU1 cDNA contained an open reading frame encoding a 425 amino acid peptide. The conserved POU domain was located near the carboxy terminus. The deduced amino acid sequence of the reading frame was most similar to that of the mouse class III POU-domain gene, Brain-1. Northern blot analysis revealed that the ZFPOU1 transcripts first appeared at the early neurula stage of embryogenesis and transiently increased thereafter. A significant level of expression, however, was not found in adult tissues except in the brain. In situ hybridization analysis demonstrated that the ZFPOU1 transcripts were localized in the neural tissues of embryos, but not in mesodermal, endodermal or ectodermal tissues. In adult zebrafish, the ZFPOU1 transcripts were detected in the restricted regions of the brain. Spatial and temporal expression patterns suggest that ZFPOU1 has distinct roles in the early neural development of zebrafish.

Amino Acid Sequence↗