Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis.
The floor plate, an essential ventral midline organizing center that produces the morphogen Shh, has distinct properties along the neuraxis. The neurogenic potential of the floor plate and its underlying mechanisms remain unknown. Using Shh as a driver for lineage analysis, we found that the mouse midbrain, but not the hindbrain, floor plate is neurogenic, giving rise to dopamine (DA) neurons. Distinct spatiotemporal Shh and Wnt expression may distinguish the neurogenetic potential of these structures. We discovered an inhibitory role for Shh: removal of Shh resulted in neurogenesis from the hindbrain midline and, conversely, high doses of Shh inhibited proliferation and DA neuron production in midbrain cultures. We found that Wnt/beta-catenin signaling is necessary and sufficient for antagonizing Shh, DA progenitor marker induction and promotion of dopaminergic neurogenesis. These findings demonstrate how the dynamic interplay of canonical Wnt/beta-catenin signaling and Shh may orchestrate floor plate neurogenesis or a lack thereof.
Joksimovic
Milan
M
Northwestern University Feinberg Medical School, Department of Neurology and Center for Genetic Medicine, 7-113 Lurie Bldg, 303 E Superior Street, Chicago, Illinois 60611, USA.
Yun
Beth A
BA
Kittappa
Raja
R
Anderegg
Angela M
AM
Chang
Wendy W
WW
Taketo
Makoto M
MM
McKay
Ronald D G
RD
Awatramani
Rajeshwar B
RB
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051857:Otx Transcription Factors / Q000378:metabolism; D011247:Pregnancy; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D055153:Stem Cell Niche / Q000166:cytology / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C496503:Foxa2 protein, mouse; C112149:LIM homeobox transcription factor 1 beta; C489692:Lmx1a protein, mouse; C102938:Neurog2 protein, mouse; C497660:Otx2 protein, mouse; C465570:Shh protein, mouse