title: Maternal transcription of non-protein coding RNAs from the PWS-critical region rescues growth retardation in mice.
abstract: Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by loss of paternally expressed genes on chromosome 15q11-q13. The PWS-critical region (PWScr) contains an array of non-protein coding IPW-A exons hosting intronic SNORD116 snoRNA genes. Deletion of PWScr is associated with PWS in humans and growth retardation in mice exhibiting ~15% postnatal lethality in C57BL/6 background. Here we analysed a knock-in mouse containing a 5'HPRT-LoxP-Neo(R) cassette (5'LoxP) inserted upstream of the PWScr. When the insertion was inherited maternally in a paternal PWScr-deletion mouse model (PWScr(p-/m5'LoxP)), we observed compensation of growth retardation and postnatal lethality. Genomic methylation pattern and expression of protein-coding genes remained unaltered at the PWS-locus of PWScr(p-/m5'LoxP) mice. Interestingly, ubiquitous Snord116 and IPW-A exon transcription from the originally silent maternal chromosome was detected. In situ hybridization indicated that PWScr(p-/m5'LoxP) mice expressed Snord116 in brain areas similar to wild type animals. Our results suggest that the lack of PWScr RNA expression in certain brain areas could be a primary cause of the growth retardation phenotype in mice. We propose that activation of disease-associated genes on imprinted regions could lead to general therapeutic strategies in associated diseases.
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Department of Medicine (TRAM), University Hospital of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Timofey S
authors: TS
authors: Rozhdestvensky
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Department of Medicine (TRAM), University Hospital of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Thomas
authors: T
authors: Robeck
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Chenna R
authors: CR
authors: Galiveti
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Institute of Evolutionary and Medical Genomics, Brandenburg Medical School (MHB), D-16816 Neuruppin, Germany.
authors: Carsten A
authors: CA
authors: Raabe
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Department of Medicine (TRAM), University Hospital of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Birte
authors: B
authors: Seeger
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Anna
authors: A
authors: Wolters
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Department of Medicine (TRAM), University Hospital of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Leonid V
authors: LV
authors: Gubar
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Institute of Evolutionary and Medical Genomics, Brandenburg Medical School (MHB), D-16816 Neuruppin, Germany.
authors: Jürgen
authors: J
authors: Brosius
authors: Institute of Experimental Pathology (ZMBE), University of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.|Department of Medicine (TRAM), University Hospital of Muenster, Von-Esmarch-Str. 56, D-48149 Münster, Germany.
authors: Boris V
authors: BV
authors: Skryabin
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D001921:Brain / Q000378:metabolism; D002895:Chromosomes, Human, Pair 5; D019175:DNA Methylation; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D055879:Gene Knock-In Techniques; D056426:Genetic Loci; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020537:RNA, Small Nucleolar / Q000235:genetics / Q000378:metabolism*
chemical_list: D020537:RNA, Small Nucleolar; C000609194:SNORD116 RNA, mouse