title: Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry.
abstract: The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp(+/-) and cbp(+/+) littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.
authors.affiliation: Center for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Ateca-Cabarga
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Cosa
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Pallarés
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.
authors.forename: José P
authors.initials: JP
authors.lastname: López-Atalaya
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Barco
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Canals
authors.affiliation: Center for Biomaterials and Tissue Engineering, Universitat Politècnica de València, Valencia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Moratal
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D050882:CREB-Binding Protein / Q000235:genetics*; D057895:Haploinsufficiency; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012415:Rubinstein-Taybi Syndrome / Q000235:genetics / Q000473:pathology*
chemical_list: D050882:CREB-Binding Protein; C494363:CREBBP protein, human