Abstract
ABSTRACTThe isthmic organizer (IsO) is a signaling center that specifies the correct and distinct embryonic development of the dopaminergic midbrain and serotonergic hindbrain. The IsO is a linear boundary between the two brain regions, emerging at around embryonic day 7-8 of murine embryonic development, that shapes its surroundings through the expression of instructive signals such as Wnt and growth factors. Homeobox transcription factor engrailed 1 (En1) is present in midbrain and rostral hindbrain (i.e. rhombomere 1, R1). Its expression spans the IsO, and it is known to be an important survival factor for both dopaminergic and serotonergic neurons. Erroneous composition of dopaminergic neurons in the midbrain or serotonergic neurons in the hindbrain is associated with severe pathologies such as Parkinson's disease, depression or autism. Here we investigated the role of En1 in early mid-hindbrain development, using multiple En1-ablated mouse models as well as lineage-tracing techniques, and observed the appearance of ectopic dopaminergic neurons, indistinguishable from midbrain dopaminergic neurons based on molecular profile and intrinsic electrophysiological properties. We propose that this change is the direct result of a caudal relocation of the IsO as represented by ectopic presence of Fgf8, Otx2, Wnt1 and canonical Wnt-signalling. Our work suggests a newly-discovered role for En1: the repression of Otx2, Wnt1 and canonical Wnt-signaling in R1. Overall, our results suggest that En1 is essential for proper IsO maintenance and function.
Highlights
The correct and distinct embryonic development of the midbrain and hindbrain is specified by a signaling center between these brain areas: the isthmic organizer (IsO)
We propose that the appearance of ectopic dopaminergic neurons is the direct result of an extension of midbrain patterning in rhombomere 1 (R1), due to a caudal relocation of the IsO as represented by ectopic presence of fibroblast growth factor 8 (Fgf8), Otx2, Wnt1 and canonical Wnt-signaling
Ectopic dopaminergic neurons arise in rostral hindbrain in absence of engrailed 1 (En1) To further substantiate our initial observations at E14.5 that in absence of En1 cells emerge in the metencephalon that possess a dopaminergic profile (Veenvliet et al, 2013) we mapped the appearance of the ectopic DA neurons in time (Fig. 1A)
Summary
The correct and distinct embryonic development of the midbrain and hindbrain is specified by a signaling center between these brain areas: the isthmic organizer (IsO). The correct function of the IsO is essential in determining the location and respective size of these neuronal systems. Swammerdam Institute for Life Sciences, University of Amsterdam, P.O. Box 94215, 1090 GE Amsterdam, The Netherlands. Box 94215, 1090 GE Amsterdam, The Netherlands
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