D. Picketts - Academia.edu (original) (raw)

Papers by D. Picketts

B FLS is a rare X linked recessive disorder characterised by moderate to severe mental retardatio... more B FLS is a rare X linked recessive disorder characterised by moderate to severe mental retardation, obesity with gynaecomastia, hypogonadism, and large prominent ears. However, a clear diagnosis is often difficult. BFLS may be confused with other obesity related mental retardation syndromes as there can be intrafamilial and interfamilial phenotypic variability and women may also be affected, possibly because of skewed X inactivation. Following the identification of the PHF6 gene (Xq26–27) as the cause of BFLS, Turner et al showed that the phenotype may be milder and broader than originally appreciated. Mutations in the PHF6 gene have been identified in 11 families and they are localised throughout the gene, suggesting a loss of function mechanism. Primary sequence analysis has suggested that PHF6 encodes a transcriptional regulator based on the presence of two PHD zinc finger domains, a motif common to chromatin remodelling proteins including the ATRX protein. Nonetheless, little is...

Cell Death and Disease, 2016

International Journal of Developmental Neuroscience, 2006

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a numb... more Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however knowledge of the role of these proteins in normal CNS development is limited. In Drosophila, ISWI is essential for development and the protein functions as the ATPhydrolysing component in several chromatin-remodeling complexes. The two mammalian ISWI orthologs, SNF2H and SNF2L are differentially expressed, suggesting that they possess distinct developmental roles. Prevalent expression of SNF2H occurs during neuroprogenitor proliferation while SNF2L transcripts have increased levels in maturing neurons. Here we use conditional Cre-loxP gene-targeting to inactivate the murine Snf2l gene in order to assess its role in neurodevelopment. Heterozygous females (Snf2l) were crossed to mice expressing Crerecombinase under the control of the GATA-1 promoter. SNF2Lnull male mice were viable and born at classic Mendelian ratios. These mice displayed no overt developmental or behavioral abnormalities; however, the loss of Snf2l resulted in a 2-fold increase in the brain weight to body weight ratio. This was accompanied by a concomitant increase in cell number in the hippocampus and cerebral cortex ranging from 0.5to 2-fold in the six distinct cortical layers and a 2-fold increase in all hippocampal strata. Moreover we observed a proportionate increase in BrdU staining of the ventricular and intermediate zones of day 15.5 embryonic cortices, coupled with an approximately 3fold increase in cells undergoing mitosis. These results suggest that the increased cell number within the adult brain arose from enhanced embryonic neuroprogenitor proliferation. Finally, loss of Snf2l protein was accompanied by an increase in Snf2h protein levels, suggesting that Snf2h can functionally compensate for the loss of Snf2l in the mutant mice. Taken together, our results indicate that a proper balance of Snf2h to Snf2l protein ratios is an important regulator of brain size and/or cell number.

Development (Cambridge, England), 2015

Midbrain dopamine neuronal progenitors develop into heterogeneous subgroups of neurons, such as s... more Midbrain dopamine neuronal progenitors develop into heterogeneous subgroups of neurons, such as substantia nigra pars compacta, ventral tegmental area and retrorubal field, that regulate motor control, motivated and addictive behaviours. The development of midbrain dopamine neurons has been extensively studied, and these studies indicate that complex cross-regulatory interactions between extrinsic and intrinsic molecules regulate a precise temporal and spatial programme of neurogenesis in midbrain dopamine progenitors. To elucidate direct molecular interactions between multiple regulatory factors during neuronal differentiation in mice, we characterised genome-wide binding sites of the forkhead/winged helix transcription factor Foxa1, which functions redundantly with Foxa2 to regulate the differentiation of mDA neurons. Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, Foxa1, Foxa2 and an E-box transcription fact...

Human molecular genetics, 1995

Mental handicap is a common clinical problem that has been a relatively neglected area of researc... more Mental handicap is a common clinical problem that has been a relatively neglected area of research. Though the causes are varied and complex, molecular biologists are making progress in understanding the mechanisms in some cases, particularly where there are distinguishing phenotypic or genetic markers. The fortuitous association of alpha thalassaemia with a form of mental retardation has allowed us to define a specific X-linked syndrome (ATR-X). Positional cloning was used to define a disease interval and examination of candidate genes demonstrated that mutations in a gene, XH2, showing homology to the SNF2 superfamily were responsible for this syndrome. The complex ATR-X phenotype suggests that this gene, when mutated, down-regulates the expression of several genes including the alpha-globin genes indicating that it could be a global transcriptional regulator. It is conceivable that this mechanism is involved in other forms of syndromal mental retardation.

Blood, 1994

Hemophilia B Leyden is a rare form of inherited factor IX deficiency in which patients experience... more Hemophilia B Leyden is a rare form of inherited factor IX deficiency in which patients experience spontaneous postpubertal recovery of factor IX levels. The mutations resulting in this disorder are localized in a 40-nucleotide region encompassing the major transcriptional start site for factor IX. Here we report the further characterization of five cis-acting elements in the factor IX promoter and the effects on protein binding and transcriptional activation of five Leyden mutations (at nucleotides +13, -5, -6, -20, and -26) that occur within the proximal three elements (sites 1 through 3). Bandshift studies using nuclear extracts from four different rat tissues have shown that at least some of the proteins binding to each of the five sites are ubiquitous in nature. The pattern of DNA binding at site 1 suggests that this element plays an important role in mediating the liver-specific expression of factor IX. Additional studies with liver nuclear extracts obtained at several differen...

Blood, 1995

We have examined the role of the major positive upstream regulatory element of the human alpha-gl... more We have examined the role of the major positive upstream regulatory element of the human alpha-globin gene locus (HS-40) in its natural chromosomal context. Using homologous recombination, HS-40 was replaced by a neo marker gene in a mouse erythroleukemia hybrid cell line containing a single copy of human chromosome 16. In clones from which HS-40 had been deleted, human alpha-globin gene expression was severely reduced, although basal levels of alpha 1 and alpha 2-globin mRNA expression representing less than 3% of the level in control cell lines were detected. Deletion of the neo marker gene, by using FLP recombinase/FLP recombinase target system, proved that the phenotype observed was not caused by the regulatory elements of this marker gene. In the targeted clones, deletion of HS-40 apparently does not affect long-range or local chromatin structure at the alpha promoters. Therefore, these results indicate that, in the experimental system used, HS-40 behaves as a strong inducible ...

The Journal of biological chemistry, Jan 15, 1989

The complete cDNA sequence of a mitochondrial protein from Chinese hamster ovary cells, designate... more The complete cDNA sequence of a mitochondrial protein from Chinese hamster ovary cells, designated P1, which was originally identified as a microtubule-related protein (Gupta, R.S., Ho, T.K.W., Moffat, M.R.K., and Gupta, R. (1982) J. Biol. Chem. 257, 1071-1078), has been determined. The P1 cDNA encodes a protein of 60,983 Da including a 26-amino acid putative mitochondrial targeting sequence at its N-terminal end. The deduced amino acid sequence of Chinese hamster P1 shows 97% identity to the human P1 protein. Most interestingly, the amino acid sequences of mammalian P1 proteins show extensive sequence homology (42-60% identical residues and an additional 15-25% conservative replacements) to the "chaperonin" family of bacterial, yeast, and plant proteins (viz. groEL protein of Escherichia coli, hsp 60 protein of yeast, and ribulose-1,5-bisphosphate carboxylase subunit binding protein of plant chloroplasts) and to the 60-65-kDa major antigenic protein of mycobacteria and Co...

Trends in Endocrinology & Metabolism, 2007

Proceedings of the National Academy of Sciences, 1999

Physiology, 2009

The heterogeneous nature of congenital hydrocephalus has hampered our understanding of the molecu... more The heterogeneous nature of congenital hydrocephalus has hampered our understanding of the molecular basis of this common clinical problem. However, disease gene identification and characterization of multiple transgenic mouse models has highlighted the importance of the subcommissural organ (SCO) and the ventricular ependymal (vel) cells. Here, we review how altered development and function of the SCO and vel cells contributes to hydrocephalus.

Molecular and Cellular Biology, 2006

The cellular inhibitor of apoptosis 2 (cIAP2/HIAP1) is a potent inhibitor of apoptotic death. In ... more The cellular inhibitor of apoptosis 2 (cIAP2/HIAP1) is a potent inhibitor of apoptotic death. In contrast to the other members of the IAP family, cIAP2 is transcriptionally inducible by nuclear factor-κB in response to multiple triggers. We demonstrate here that cIAP2−/− mice exhibit profound resistance to lipopolysaccharide (LPS)-induced sepsis, specifically because of an attenuated inflammatory response. We show that LPS potently upregulates cIAP2 in macrophages and that cIAP2−/− macrophages are highly susceptible to apoptosis in a LPS-induced proinflammatory environment. Hence, cIAP2 is critical in the maintenance of a normal innate immune inflammatory response.

Mammalian Genome, 1998

... Comparison of the human and murine ATRX gene identifies highly conserved, functionally import... more ... Comparison of the human and murine ATRX gene identifies highly conserved, functionally important domains David J. Picketts,&amp;amp;#x27; Ayse 0. Tastan,2 Douglas R. Higgs,&amp;amp;#x27; Richard J. Gibbons&amp;amp;#x27; ... 403 region of ATRX and a new protein (PIX1) was recently reported (Cardoso et al. 1997). ...

Journal of Neurochemistry, 2001

Here we report the cloning of two cDNAs, Snf2h and Snf2l, encoding the murine members of the Imit... more Here we report the cloning of two cDNAs, Snf2h and Snf2l, encoding the murine members of the Imitation Switch (ISWI) family of chromatin remodeling proteins. To gain insight into their function we examined the spatial and temporal expression patterns of Snf2h and Snf2l during development. In the brain, Snf2h is prevalent in proliferating cell populations whereas, Snf2l is predominantly expressed in terminally differentiated neurons after birth and in adult animals, concomitant with the expression of a neural specific isoform. Moreover, a similar proliferation/differentiation relationship of expression for these two genes was observed in the ovaries and testes of adult mice. These results are consistent with a role of Snf2h complexes in replication-associated nucleosome assembly and suggest that Snf2l complexes have distinct functions associated with cell maturation or differentiation.