Andrew E Baltus | Children's Hospital Boston (original) (raw)
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Papers by Andrew E Baltus
The American Journal of …, Jan 1, 2008
Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also ... more Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also referenced as Woodhouse-Sakati syndrome) is a rare autosomal recessive multisystemic disorder. We have identified a founder mutation consisting of a single base-pair deletion in C2orf37 in eight families of Saudi origin. Three other loss-of-function mutations were subsequently discovered in patients of different ethnicities. The gene encodes a nucleolar protein of unknown function, and the cellular phenotype observed in patient lymphoblasts implicates a role for the nucleolus in the pathogenesis of this disease. Our findings expand the list of human disorders linked to the nucleolus and further highlight the developmental and/or maintenance functions of this organelle.
Journal of …, Jan 1, 2001
Synaptotagmin has been proposed to function as a Ca(2+) sensor that regulates synaptic vesicle ex... more Synaptotagmin has been proposed to function as a Ca(2+) sensor that regulates synaptic vesicle exocytosis, whereas the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is thought to form the core of a conserved membrane fusion machine. Little is known concerning the functional relationships between synaptotagmin and SNAREs. Here we report that synaptotagmin can facilitate SNARE complex formation in vitro and that synaptotagmin mutations disrupt SNARE complex formation in vivo. Synaptotagmin oligomers efficiently bind SNARE complexes, whereas Ca(2+) acting via synaptotagmin triggers cross-linking of SNARE complexes into dimers. Mutations in Drosophila that delete the C2B domain of synaptotagmin disrupt clathrin AP-2 binding and endocytosis. In contrast, a mutation that blocks Ca(2+)-triggered conformational changes in C2B and diminishes Ca(2+)-triggered synaptotagmin oligomerization results in a postdocking defect in neurotransmitter release and a decrease in SNARE assembly in vivo. These data suggest that Ca(2+)-driven oligomerization via the C2B domain of synaptotagmin may trigger synaptic vesicle fusion via the assembly and clustering of SNARE complexes.
Nature genetics, Jan 1, 2006
Nature genetics, Jan 1, 2004
We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive... more We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive spermatogenic defect mapped to mouse chromosome 1 (refs. 1,2). We localized jsd to a 272-kb region and resequenced this area to identify the underlying mutation: a frameshift that severely truncates the predicted protein product of a 2.3-kb genomic open reading frame. This gene, Utp14b, evidently arose through reverse transcription of an mRNA from an X-linked gene and integration of the resulting cDNA into an intron of an autosomal gene, whose promoter and 5′ untranslated exons are shared with Utp14b. To our knowledge, Utp14b is the first protein-coding retrogene to be linked to a recessive mammalian phenotype. The X-linked progenitor of Utp14b is the mammalian ortholog of yeast Utp14, which encodes a protein required for processing of pre-rRNA 3 and hence for ribosome assembly. Our findings substantiate the hypothesis 4 that mammalian spermatogenesis is supported by autosomal retrogenes that evolved from X-linked housekeeping genes to compensate for silencing of the X chromosome during male meiosis 5-7 . We find that Utp14b-like retrogenes arose independently and were conserved during evolution in at least four mammalian lineages. This recurrence implies a strong selective pressure, perhaps to enable ribosome assembly in male meiotic cells.
Proceedings of the …, Jan 1, 2008
In eukaryotes, diploid cells give rise to haploid cells via meiosis, a program of two cell divisi... more In eukaryotes, diploid cells give rise to haploid cells via meiosis, a program of two cell divisions preceded by one round of DNA replication. Although key molecular components of the meiotic apparatus are highly conserved among eukaryotes, the mechanisms responsible for initiating the meiotic program have diverged substantially among eukaryotes. This raises a related question in animals with two distinct sexes: Within a given species, are similar or different mechanisms of meiotic initiation used in the male and female germ lines? In mammals, this question is underscored by dramatic differences in the timing of meiotic initiation in males and females. Stra8 is a vertebrate-specific, cytoplasmic factor expressed by germ cells in response to retinoic acid. We previously demonstrated that Stra8 gene function is required for meiotic initiation in mouse embryonic ovaries. Here we report that, on an inbred C57BL/6 genetic background, the same factor is also required for meiotic initiation in germ cells of juvenile mouse testes. In juvenile C57BL/6 males lacking Stra8 gene function, the early mitotic development of germ cells appears to be undisturbed. However, these cells then fail to undergo the morphological changes that define meiotic prophase, and they do not display the molecular hallmarks of meiotic chromosome cohesion, synapsis and recombination. We conclude that, in mice, Stra8 regulates meiotic initiation in both spermatogenesis and oogenesis. Taken together with previous observations, our present findings indicate that, in both the male and female germ lines, meiosis is initiated through retinoic acid induction of Stra8.
Developmental …, Jan 1, 2001
Human beta-catenin and its fly homolog Armadillo are best known for their roles in cadherin-based... more Human beta-catenin and its fly homolog Armadillo are best known for their roles in cadherin-based cell-cell adhesion and in transduction of Wingless/Wnt signals. It has been hypothesized that beta-catenin may also regulate cell migration and cell shape changes, possibly by regulating the microtubule cytoskeleton via interactions with APC. This hypothesis was based on experiments in which a hyperstable mutant form of beta-catenin was expressed in MDCK cells, where it altered their migratory properties and their ability to send out long cellular processes. We tested the generality of this hypothesis in vivo in Drosophila. We utilized three model systems in which cell migration and/or process extension are known to play key roles during development: the migration of the border cells during oogenesis, the extension of axons in the nervous system, and the migration and cell process extension of tracheal cells. In all cases, cells expressing activated Armadillo were able to migrate and extend cell processes essentially normally. The one alteration from normal involved an apparent cell fate change in certain tracheal cells. These results suggest that only certain cells are affected by activation of Armadillo/beta-catenin, and that Armadillo/beta-catenin does not play a general role in inhibiting cell migration or process extension.
Page 1. Developmental Transitions of the Germ Cell Lineage of the Mouse by Andrew Edmund Baltus B... more Page 1. Developmental Transitions of the Germ Cell Lineage of the Mouse by Andrew Edmund Baltus BS Genetics University of Wisconsin - Madison, 2000 SUBMITTED TO THE DEPARTMENT OF BIOLOGY IN PARTIAL FULFILLMENT ...
The American Journal of …, Jan 1, 2008
Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also ... more Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also referenced as Woodhouse-Sakati syndrome) is a rare autosomal recessive multisystemic disorder. We have identified a founder mutation consisting of a single base-pair deletion in C2orf37 in eight families of Saudi origin. Three other loss-of-function mutations were subsequently discovered in patients of different ethnicities. The gene encodes a nucleolar protein of unknown function, and the cellular phenotype observed in patient lymphoblasts implicates a role for the nucleolus in the pathogenesis of this disease. Our findings expand the list of human disorders linked to the nucleolus and further highlight the developmental and/or maintenance functions of this organelle.
Journal of …, Jan 1, 2001
Synaptotagmin has been proposed to function as a Ca(2+) sensor that regulates synaptic vesicle ex... more Synaptotagmin has been proposed to function as a Ca(2+) sensor that regulates synaptic vesicle exocytosis, whereas the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is thought to form the core of a conserved membrane fusion machine. Little is known concerning the functional relationships between synaptotagmin and SNAREs. Here we report that synaptotagmin can facilitate SNARE complex formation in vitro and that synaptotagmin mutations disrupt SNARE complex formation in vivo. Synaptotagmin oligomers efficiently bind SNARE complexes, whereas Ca(2+) acting via synaptotagmin triggers cross-linking of SNARE complexes into dimers. Mutations in Drosophila that delete the C2B domain of synaptotagmin disrupt clathrin AP-2 binding and endocytosis. In contrast, a mutation that blocks Ca(2+)-triggered conformational changes in C2B and diminishes Ca(2+)-triggered synaptotagmin oligomerization results in a postdocking defect in neurotransmitter release and a decrease in SNARE assembly in vivo. These data suggest that Ca(2+)-driven oligomerization via the C2B domain of synaptotagmin may trigger synaptic vesicle fusion via the assembly and clustering of SNARE complexes.
Nature genetics, Jan 1, 2006
Nature genetics, Jan 1, 2004
We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive... more We identified the gene carrying the juvenile spermatogonial depletion mutation (jsd), a recessive spermatogenic defect mapped to mouse chromosome 1 (refs. 1,2). We localized jsd to a 272-kb region and resequenced this area to identify the underlying mutation: a frameshift that severely truncates the predicted protein product of a 2.3-kb genomic open reading frame. This gene, Utp14b, evidently arose through reverse transcription of an mRNA from an X-linked gene and integration of the resulting cDNA into an intron of an autosomal gene, whose promoter and 5′ untranslated exons are shared with Utp14b. To our knowledge, Utp14b is the first protein-coding retrogene to be linked to a recessive mammalian phenotype. The X-linked progenitor of Utp14b is the mammalian ortholog of yeast Utp14, which encodes a protein required for processing of pre-rRNA 3 and hence for ribosome assembly. Our findings substantiate the hypothesis 4 that mammalian spermatogenesis is supported by autosomal retrogenes that evolved from X-linked housekeeping genes to compensate for silencing of the X chromosome during male meiosis 5-7 . We find that Utp14b-like retrogenes arose independently and were conserved during evolution in at least four mammalian lineages. This recurrence implies a strong selective pressure, perhaps to enable ribosome assembly in male meiotic cells.
Proceedings of the …, Jan 1, 2008
In eukaryotes, diploid cells give rise to haploid cells via meiosis, a program of two cell divisi... more In eukaryotes, diploid cells give rise to haploid cells via meiosis, a program of two cell divisions preceded by one round of DNA replication. Although key molecular components of the meiotic apparatus are highly conserved among eukaryotes, the mechanisms responsible for initiating the meiotic program have diverged substantially among eukaryotes. This raises a related question in animals with two distinct sexes: Within a given species, are similar or different mechanisms of meiotic initiation used in the male and female germ lines? In mammals, this question is underscored by dramatic differences in the timing of meiotic initiation in males and females. Stra8 is a vertebrate-specific, cytoplasmic factor expressed by germ cells in response to retinoic acid. We previously demonstrated that Stra8 gene function is required for meiotic initiation in mouse embryonic ovaries. Here we report that, on an inbred C57BL/6 genetic background, the same factor is also required for meiotic initiation in germ cells of juvenile mouse testes. In juvenile C57BL/6 males lacking Stra8 gene function, the early mitotic development of germ cells appears to be undisturbed. However, these cells then fail to undergo the morphological changes that define meiotic prophase, and they do not display the molecular hallmarks of meiotic chromosome cohesion, synapsis and recombination. We conclude that, in mice, Stra8 regulates meiotic initiation in both spermatogenesis and oogenesis. Taken together with previous observations, our present findings indicate that, in both the male and female germ lines, meiosis is initiated through retinoic acid induction of Stra8.
Developmental …, Jan 1, 2001
Human beta-catenin and its fly homolog Armadillo are best known for their roles in cadherin-based... more Human beta-catenin and its fly homolog Armadillo are best known for their roles in cadherin-based cell-cell adhesion and in transduction of Wingless/Wnt signals. It has been hypothesized that beta-catenin may also regulate cell migration and cell shape changes, possibly by regulating the microtubule cytoskeleton via interactions with APC. This hypothesis was based on experiments in which a hyperstable mutant form of beta-catenin was expressed in MDCK cells, where it altered their migratory properties and their ability to send out long cellular processes. We tested the generality of this hypothesis in vivo in Drosophila. We utilized three model systems in which cell migration and/or process extension are known to play key roles during development: the migration of the border cells during oogenesis, the extension of axons in the nervous system, and the migration and cell process extension of tracheal cells. In all cases, cells expressing activated Armadillo were able to migrate and extend cell processes essentially normally. The one alteration from normal involved an apparent cell fate change in certain tracheal cells. These results suggest that only certain cells are affected by activation of Armadillo/beta-catenin, and that Armadillo/beta-catenin does not play a general role in inhibiting cell migration or process extension.
Page 1. Developmental Transitions of the Germ Cell Lineage of the Mouse by Andrew Edmund Baltus B... more Page 1. Developmental Transitions of the Germ Cell Lineage of the Mouse by Andrew Edmund Baltus BS Genetics University of Wisconsin - Madison, 2000 SUBMITTED TO THE DEPARTMENT OF BIOLOGY IN PARTIAL FULFILLMENT ...