Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI

With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17(-/-)) have anatomical abnormalities in the inferior colliculus (IC)-the auditory midbrain-and minor foliation defects in the cerebellum. In addition, changes in the expression domains of several cortical patterning genes were detected, without overt changes in forebrain morphology. Recently, it has also been reported that Fgf17(-/-) mutants have abnormal vocalization and social behaviors, phenotypes that could reflect molecular changes in the cortex and/or altered auditory processing / perception in these mice. We used manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) to analyze the anatomical phenotype of Fgf17(-/-) mutants in more detail than achieved previously, detecting changes in IC, cerebellum, olfactory bulb, hypothalamus and frontal cortex. We also used MEMRI to characterize sound-evoked activity patterns, demonstrating a significant reduction of the active IC volume in Fgf17(-/-) mice. Furthermore, tone-specific (16- and 40-kHz) activity patterns in the IC of Fgf17(-/-) mice were observed to be largely overlapping, in contrast to the normal pattern, separated along the dorsal-ventral axis. These results demonstrate that Fgf17 plays important roles in both the anatomical and functional development of the auditory midbrain, and show the utility of MEMRI for in vivo analyses of mutant mice with subtle brain defects.

[1]  G. Ehret,et al.  Development of tonotopy in the inferior colliculus. I. Electrophysiological mapping in house mice. , 1990, Brain research. Developmental brain research.

[2]  P. Doherty,et al.  Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain. , 1999, Development.

[3]  B. Hogan,et al.  Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo , 1998, Mechanisms of Development.

[4]  J. Rubenstein,et al.  Frontal cortex subdivision patterning is coordinately regulated by Fgf8, Fgf17, and Emx2 , 2008, The Journal of comparative neurology.

[5]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[6]  F. Huang,et al.  Characterization of a 7.5-kDa protein kinase C substrate (RC3 protein, neurogranin) from rat brain. , 1993, Archives of biochemistry and biophysics.

[7]  L. Mucke,et al.  Abnormal social behaviors in mice lacking Fgf17 , 2008, Genes, brain, and behavior.

[8]  A. McMahon,et al.  Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. , 1997, Development.

[9]  R. Henkelman,et al.  Mouse behavioral mutants have neuroimaging abnormalities , 2007, Human brain mapping.

[10]  G. Martin,et al.  An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination , 1998, Nature Genetics.

[11]  J. Rubenstein,et al.  Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants , 2003, Development.

[12]  G. Martin,et al.  Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. , 1999, Genes & development.

[13]  J. Rubenstein,et al.  Patterning of frontal cortex subdivisions by Fgf17 , 2007, Proceedings of the National Academy of Sciences.

[14]  E. Grove,et al.  Neocortex Patterning by the Secreted Signaling Molecule FGF8 , 2001, Science.

[15]  D. Turnbull,et al.  In vivo auditory brain mapping in mice with Mn-enhanced MRI , 2005, Nature Neuroscience.

[16]  Wolfgang Wurst,et al.  The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum , 2003, Development.

[17]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[18]  A. Koretsky,et al.  Manganese ion enhances T1‐weighted MRI during brain activation: An approach to direct imaging of brain function , 1997, Magnetic resonance in medicine.

[19]  Scott T. Grafton,et al.  Automated image registration: I. General methods and intrasubject, intramodality validation. , 1998, Journal of computer assisted tomography.

[20]  C. MacArthur,et al.  Genomic structure, mapping, activity and expression of fibroblast growth factor 17 , 1999, Mechanisms of Development.

[21]  M. Konishi,et al.  Structure and expression of a novel fibroblast growth factor, FGF-17, preferentially expressed in the embryonic brain. , 1998, Biochemical and biophysical research communications.

[22]  Alan C. Evans,et al.  A three-dimensional MRI atlas of the mouse brain with estimates of the average and variability. , 2005, Cerebral cortex.

[23]  A. Joyner,et al.  FGF17b and FGF18 have different midbrain regulatory properties from FGF8b or activated FGF receptors , 2003, Development.

[24]  R. Mark Henkelman,et al.  Automated deformation analysis in the YAC128 Huntington disease mouse model , 2008, NeuroImage.

[25]  Xin Yu,et al.  Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI , 2008, NeuroImage.

[26]  J. Mallet,et al.  Neurogranin is locally concentrated in rat cortical and hippocampal neurons , 1996, Brain Research.

[27]  R Mark Henkelman,et al.  Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography. , 2006, Physiological genomics.

[28]  J. Rubenstein,et al.  Inductive interactions direct early regionalization of the mouse forebrain. , 1997, Development.

[29]  Salvador Martinez,et al.  Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers , 2006, Development.

[30]  H. Nakamura,et al.  Inductive signal and tissue responsiveness defining the tectum and the cerebellum. , 2001, Development.

[31]  Orlando Aristizabal,et al.  Large-scale reorganization of the tonotopic map in mouse auditory midbrain revealed by MRI , 2007, Proceedings of the National Academy of Sciences.

[32]  Salvador Martinez,et al.  Midbrain development induced by FGF8 in the chick embryo , 1996, Nature.

[33]  J. Rubenstein,et al.  FGF and Shh Signals Control Dopaminergic and Serotonergic Cell Fate in the Anterior Neural Plate , 1998, Cell.

[34]  E. Grove,et al.  Emx2 patterns the neocortex by regulating FGF positional signaling , 2003, Nature Neuroscience.

[35]  M. Brand,et al.  A series of no isthmus (noi) alleles of the zebrafish pax2.1 gene reveals multiple signaling events in development of the midbrain-hindbrain boundary. , 1998, Development.

[36]  J. Willott.  Measurement of the Auditory Brainstem Response (ABR) to Study Auditory Sensitivity in Mice , 2006, Current protocols in neuroscience.

[37]  S. Schulte-Merker,et al.  Overlapping and distinct functions provided by fgf17, a new zebrafish member of the Fgf8/17/18 subgroup of Fgfs , 2000, Mechanisms of Development.

[38]  D. Ornitz,et al.  Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures. , 2000, Development.

[39]  Kerstin Pannek,et al.  Comparative mouse brain tractography of diffusion magnetic resonance imaging , 2010, NeuroImage.

[40]  A. Joyner,et al.  Specific regions within the embryonic midbrain and cerebellum require different levels of FGF signaling during development , 2008, Development.