3D mapping of neuronal migration in the embryonic mouse brain with magnetic resonance microimaging

A prominent feature of the developing mammalian brain is the widespread migration of neural progenitor (NP) cells during embryogenesis. A striking example is provided by NP cells born in the ventral forebrain of mid-gestation stage mice, which subsequently migrate long distances to their final positions in the cortex and olfactory bulb. Previous studies have used two-dimensional histological methods, making it difficult to analyze three-dimensional (3D) migration patterns. Unlike histology, magnetic resonance microimaging (micro-MRI) is a non-destructive, quantitative and inherently 3D imaging method for analyzing mouse embryos. To allow mapping of migrating NP cells with micro-MRI, cells were labeled in situ in the medial (MGE) and lateral (LGE) ganglionic eminences, using targeted in utero ultrasound-guided injection of micron-sized particles of iron-oxide (MPIO). Ex vivo micro-MRI and histology were then performed 5-6days after injection, demonstrating that the MPIO had magnetically labeled the migrating NP populations, which enabled 3D visualization and automated segmentation of the labeled cells. This approach was used to analyze the distinct patterns of migration from the MGE and LGE, and to construct rostral-caudal migration maps from each progenitor region. Furthermore, abnormal migratory phenotypes were observed in Nkx2.1(-/-) embryos, most notably a significant increase in cortical neurons derived from the Nkx2.1(-/-) LGE. Taken together, these results demonstrate that MPIO labeling and micro-MRI provide an efficient and powerful approach for analyzing 3D cell migration patterns in the normal and mutant mouse embryonic brain.

[1]  Alan P. Koretsky,et al.  In vivo labeling of adult neural progenitors for MRI with micron sized particles of iron oxide: Quantification of labeled cell phenotype , 2009, NeuroImage.

[2]  Daniel H Turnbull,et al.  Ultrasound and magnetic resonance microimaging of mouse development. , 2010, Methods in enzymology.

[3]  Susumu Mori,et al.  MRI in mouse developmental biology , 2007, NMR in biomedicine.

[4]  G. Miyoshi,et al.  Genetic Fate Mapping Reveals That the Caudal Ganglionic Eminence Produces a Large and Diverse Population of Superficial Cortical Interneurons , 2010, The Journal of Neuroscience.

[5]  Palma Iannarelli,et al.  Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage , 2006, Nature Neuroscience.

[6]  S. Anderson,et al.  Origins of Cortical Interneuron Subtypes , 2004, The Journal of Neuroscience.

[7]  G. Fishell,et al.  In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. , 2001, Development.

[8]  Jian Yang,et al.  In vivo MRI of endogenous stem/progenitor cell migration from subventricular zone in normal and injured developing brains , 2009, NeuroImage.

[9]  G. Fishell,et al.  Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. , 2001, Development.

[10]  O. Marín,et al.  Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. , 1999, Development.

[11]  S. Anderson,et al.  Distinct cortical migrations from the medial and lateral ganglionic eminences. , 2001, Development.

[12]  Alan P Koretsky,et al.  Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells. , 2003, Blood.

[13]  Yu-Chung N. Cheng,et al.  Magnetic Resonance Imaging: Physical Principles and Sequence Design , 1999 .

[14]  Daniel H. Turnbull,et al.  In vivo MRI of neural cell migration dynamics in the mouse brain , 2010, NeuroImage.

[15]  Youssef Zaim Wadghiri,et al.  Mn enhancement and respiratory gating for in utero MRI of the embryonic mouse central nervous system , 2008, Magnetic resonance in medicine.

[16]  Daniel H Turnbull,et al.  Alteration of limb and brain patterning in early mouse embryos by ultrasound-guided injection of Shh-expressing cells , 1998, Mechanisms of Development.

[17]  G. Fishell,et al.  The Temporal and Spatial Origins of Cortical Interneurons Predict Their Physiological Subtype , 2005, Neuron.

[18]  Prodromos Parasoglou,et al.  In utero phenotyping of mouse embryonic vasculature with MRI , 2012, Magnetic resonance in medicine.

[19]  Daniel H Turnbull,et al.  Specification of Mouse Telencephalic and Mid-Hindbrain Progenitors Following Heterotopic Ultrasound-Guided Embryonic Transplantation , 1997, Neuron.

[20]  Paul Strauss,et al.  Magnetic Resonance Imaging Physical Principles And Sequence Design , 2016 .

[21]  C H Fox,et al.  The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. , 1996, Genes & development.

[22]  Alan P Koretsky,et al.  Sizing it up: Cellular MRI using micron‐sized iron oxide particles , 2005, Magnetic resonance in medicine.

[23]  S. Anderson,et al.  Origin and Molecular Specification of Striatal Interneurons , 2000, The Journal of Neuroscience.

[24]  Dustin Scheinost,et al.  Serial monitoring of endogenous neuroblast migration by cellular MRI , 2011, NeuroImage.

[25]  Alan P. Koretsky,et al.  Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain , 2006, NeuroImage.

[26]  Prodromos Parasoglou,et al.  High‐resolution MRI of early‐stage mouse embryos , 2013, NMR in biomedicine.

[27]  Annemarie van der Linden,et al.  MRI visualization of endogenous neural progenitor cell migration along the RMS in the adult mouse brain: Validation of various MPIO labeling strategies , 2010, NeuroImage.

[28]  I. Cobos,et al.  Cellular patterns of transcription factor expression in developing cortical interneurons. , 2006, Cerebral cortex.