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Front Neuroanat. 2017 Oct 4;11:86. doi: 10.3389/fnana.2017.00086. eCollection 2017.

Cerebellar Vermis and Midbrain Hypoplasia Upon Conditional Deletion of Chd7 from the Embryonic Mid-Hindbrain Region.

Author information

1
Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom.
2
Department of Medical Biophysics, University of Toronto, Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
3
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
4
MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
5
MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.
6
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Abstract

Reduced fibroblast growth factor (FGF) signaling from the mid-hindbrain or isthmus organizer (IsO) during early embryonic development results in hypoplasia of the midbrain and cerebellar vermis. We previously reported evidence for reduced Fgf8 expression and FGF signaling in the mid-hindbrain region of embryos heterozygous for Chd7, the gene mutated in CHARGE (Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genitourinary anomalies and Ear defects) syndrome. However, Chd7+/- animals only exhibit mild cerebellar vermis anomalies. As homozygous deletion of Chd7 is embryonic lethal, we conditionally deleted Chd7 from the early embryonic mid-hindbrain region to identify the function of CHD7 in mid-hindbrain development. Using a combination of high resolution structural MRI and histology, we report striking midbrain and cerebellar vermis hypoplasia in the homozygous conditional mutants. We show that cerebellar vermis hypoplasia is associated with reduced embryonic Fgf8 expression and an expanded roof plate in rhombomere 1 (r1). These findings identify an essential role for Chd7 in regulating mid-hindbrain development via Fgf8.

KEYWORDS:

CHD7; cerebellum; hypoplasia; mid-hindbrain; vermis

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