Frizzled3 Controls Axonal Polarity and Intermediate Target Entry during Striatal Pathway Development.
The striatum is a large brain nucleus with an important role in the control of movement and emotions. Medium spiny neurons (MSNs) are striatal output neurons forming prominent descending axon tracts that target different brain nuclei. However, how MSN axon tracts in the forebrain develop remains poorly understood. Here, we implicate the Wnt binding receptor Frizzled3 in several uncharacterized aspects of MSN pathway formation [i.e., anterior-posterior guidance of MSN axons in the striatum and their subsequent growth into the globus pallidus (GP), an important (intermediate) target]. In Frizzled3 knock-out mice, MSN axons fail to extend along the anterior-posterior axis of the striatum, and many do not reach the GP. Wnt5a acts as an attractant for MSN axons in vitro, is expressed in a posterior high, anterior low gradient in the striatum, and Wnt5a knock-out mice phenocopy striatal anterior-posterior defects observed in Frizzled3 mutants. This suggests that Wnt5a controls anterior-posterior guidance of MSN axons through Frizzled3. Axons that reach the GP in Frizzled3 knock-out mice fail to enter this structure. Surprisingly, entry of MSN axons into the GP non-cell-autonomously requires Frizzled3, and our data suggest that GP entry may be contingent on the correct positioning of "corridor" guidepost cells for thalamocortical axons by Frizzled3. Together, these data dissect MSN pathway development and reveal (non)cell-autonomous roles for Frizzled3 in MSN axon guidance. Further, they are the first to identify a gene that provides anterior-posterior axon guidance in a large brain nucleus and link Frizzled3 to corridor cell development.


CONCLUSIONS
Striatal axon pathways mediate complex physiological functions and are an important therapeutic target, underscoring the need to define how these connections are established. Remarkably, the molecular programs regulating striatal pathway development remain poorly characterized. Here, we determine the embryonic ontogeny of the two main striatal pathways (striatonigral and striatopallidal) and identify novel (non)cell-autonomous roles for the axon guidance receptor Frizzled3 in uncharacterized aspects of striatal pathway formation (i.e., anterior-posterior axon guidance in the striatum and axon entry into the globus pallidus). Further, our results link Frizzled3 to corridor guidepost cell development and suggest that an abnormal distribution of these cells has unexpected, widespread effects on the development of different axon tracts (i.e., striatal and thalamocortical axons).
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
Francesca
F
Morello
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
Asheeta A
http://orcid.org/0000-0001-9752-8175
AA
Prasad
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
Kati
K
Rehberg
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
Renata
R
Vieira de Sá
Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain, and.
Noelia
N
Antón-Bolaños
Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain, and.
Eduardo
E
Leyva-Diaz
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
Youri
Y
Adolfs
Institute of Neuroscience, Université Catholique de Louvain, Institute of Neuroscience, Brussels 1200, Belgium.
Fadel
http://orcid.org/0000-0002-9292-6622
F
Tissir
Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain, and.
Guillermina
G
López-Bendito
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands, r.j.pasterkamp@umcutrecht.nl.
R Jeroen
RJ
Pasterkamp
D000818:Animals; D001369:Axons / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000196:embryology; D004622:Embryo, Mammalian; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D005917:Globus Pallidus / Q000166:cytology; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000196:embryology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C000600618:DRD2 protein, mouse; D051157:Frizzled Receptors; C486339:Fzd3 protein, mouse; D018398:Homeodomain Proteins; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; C433629:homeobox protein PITX3; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse
Frizzled3; axon guidance; corridor cell; development; striatum