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Sonic hedgehog is a chemoattractant for midbrain dopaminergic axons.

Hammond R, Blaess S, Abeliovich A - PLoS ONE (2009)

Bottom Line: Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient.In addition to the role of Shh in the induction of mDN precursors, Shh plays an important role in dopaminergic axon pathfinding to rostral target tissues.Furthermore, Shh signaling is involved in determining the structural diversity of these dopaminergic projections.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Center for Neurobiology and Behavior and Taub Institute, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.

ABSTRACT
Midbrain dopaminergic axons project from the substantia nigra (SN) and the ventral tegmental area (VTA) to rostral target tissues, including the striatum, pallidum, and hypothalamus. The axons from the medially located VTA project primarily to more medial target tissues in the forebrain, whereas the more lateral SN axons project to lateral targets including the dorsolateral striatum. This structural diversity underlies the distinct functions of these pathways. Although a number of guidance cues have been implicated in the formation of the distinct axonal projections of the SN and VTA, the molecular basis of their diversity remains unclear. Here we investigate the molecular basis of structural diversity in mDN axonal projections. We find that Sonic Hedgehog (Shh) is expressed at a choice point in the course of the rostral dopaminergic projections. Furthermore, in midbrain explants, dopaminergic projections are attracted to a Shh source. Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient. In addition to the role of Shh in the induction of mDN precursors, Shh plays an important role in dopaminergic axon pathfinding to rostral target tissues. Furthermore, Shh signaling is involved in determining the structural diversity of these dopaminergic projections.

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Sonic Hedgehog signaling is a candidate guidance cue for mDNs.(A, B) Immunohistochemical analysis of Sonic Hedgehog (Shh) and Smoothened (Smo) expression in relation to the tyrosine hydroxylase (TH)- positive midbrain dopaminergic neurons (mDN) in E12.5 mouse embryos. (A) Shh expression in the ventral midline of the midbrain (mb) ventricular zone (indicated by arrowhead in left panel) lies dorsal to differentiated mDN (TH+). Shh expression in the hypothalamus (hyp) lies ventral and rostral to the dopaminergic cell bodies (indicated by arrow in left panel). Note that TH+ mDN axonal projections are found in the Shh expressing region in the hypothalamus (arrows in right panel). The right panel, a higher magnification of the boxed area in the merged image, is a maximum intensity projection of a Z-stack acquired with the Zeiss ApoTome system. Asterisks in merged image indicate background staining of blood vessels. Aqueduct is outlined. Immunostaining was performed on coronal sections. The plane of section is indicated in schematic in D. (B) Smo expression co-localizes with the midbrain dopaminergic population. Immunostaining was performed on sagittal sections. The area shown is indicated in the schematic in D. (C) Mid-sagittal sections of E12.5 embryonic brain. Arrows indicate location of dopaminergic neurons. The area shown is indicated in the schematic in D. TH/Hoechst: Immunostaining for TH and Hoechst showing the location of dopaminergic neurons (arrow) in relation to the aqueduct (aq) and 3rd ventricle (vt) (outlined) and the mid/hindbrain boundary (MHB). Ptc: Analysis of Ptc-lacZ [18] mice by X-gal staining for β-galactosidase activity shows expression of Patched in the ventral midbrain. Blue staining indicates Ptc-lacZ expression, pink staining is a nuclear stain (nuclear fast red). Smo: In situ hybridization for Smo shows expression of Smo in the ventral midbrain. Shh: In situ hybridization for Shh shows expression dorsal (in mb) and rostral (in hyp) to the mDN cell population. (D) Schematic of sagittal (left panel) and transverse sections (right panels) of midbrain at E12.5. Lateral SN neuronal projections that course to the dorsolateral striatum precursor are in green. Medial ventral projections from the VTA, which project to the nucleus accumbens precursor, are in red. Additional medial fibers project ventrally to the pallidum. Pink line depicts the floor plate and ventral midline. Sagittal schematic: Brown line displays the midbrain-hindbrain junction. Dashed line corresponds to the orientation of the transverse section in A. Black box depicts the sagittal sections in B. Dashed box depict sagittal sections in C. Transverse schematic: Green and red circles in midbrain depict mDN cell bodies, small green and red circles in hypothalamus depict mDN axonal projections. Scale bars: (A) 100 µm (merge) and 20 µm (high mag); (B) 50 µm; (C) 200 µm.
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pone-0007007-g001: Sonic Hedgehog signaling is a candidate guidance cue for mDNs.(A, B) Immunohistochemical analysis of Sonic Hedgehog (Shh) and Smoothened (Smo) expression in relation to the tyrosine hydroxylase (TH)- positive midbrain dopaminergic neurons (mDN) in E12.5 mouse embryos. (A) Shh expression in the ventral midline of the midbrain (mb) ventricular zone (indicated by arrowhead in left panel) lies dorsal to differentiated mDN (TH+). Shh expression in the hypothalamus (hyp) lies ventral and rostral to the dopaminergic cell bodies (indicated by arrow in left panel). Note that TH+ mDN axonal projections are found in the Shh expressing region in the hypothalamus (arrows in right panel). The right panel, a higher magnification of the boxed area in the merged image, is a maximum intensity projection of a Z-stack acquired with the Zeiss ApoTome system. Asterisks in merged image indicate background staining of blood vessels. Aqueduct is outlined. Immunostaining was performed on coronal sections. The plane of section is indicated in schematic in D. (B) Smo expression co-localizes with the midbrain dopaminergic population. Immunostaining was performed on sagittal sections. The area shown is indicated in the schematic in D. (C) Mid-sagittal sections of E12.5 embryonic brain. Arrows indicate location of dopaminergic neurons. The area shown is indicated in the schematic in D. TH/Hoechst: Immunostaining for TH and Hoechst showing the location of dopaminergic neurons (arrow) in relation to the aqueduct (aq) and 3rd ventricle (vt) (outlined) and the mid/hindbrain boundary (MHB). Ptc: Analysis of Ptc-lacZ [18] mice by X-gal staining for β-galactosidase activity shows expression of Patched in the ventral midbrain. Blue staining indicates Ptc-lacZ expression, pink staining is a nuclear stain (nuclear fast red). Smo: In situ hybridization for Smo shows expression of Smo in the ventral midbrain. Shh: In situ hybridization for Shh shows expression dorsal (in mb) and rostral (in hyp) to the mDN cell population. (D) Schematic of sagittal (left panel) and transverse sections (right panels) of midbrain at E12.5. Lateral SN neuronal projections that course to the dorsolateral striatum precursor are in green. Medial ventral projections from the VTA, which project to the nucleus accumbens precursor, are in red. Additional medial fibers project ventrally to the pallidum. Pink line depicts the floor plate and ventral midline. Sagittal schematic: Brown line displays the midbrain-hindbrain junction. Dashed line corresponds to the orientation of the transverse section in A. Black box depicts the sagittal sections in B. Dashed box depict sagittal sections in C. Transverse schematic: Green and red circles in midbrain depict mDN cell bodies, small green and red circles in hypothalamus depict mDN axonal projections. Scale bars: (A) 100 µm (merge) and 20 µm (high mag); (B) 50 µm; (C) 200 µm.

Mentions: Mammalian mDN axonal projections course rostrally towards forebrain structures that are expanded in both the dorsoventral and mediolateral axes. The most medial and ventral mDN projections, within the VTA, regulate reward-associated behavior and novelty learning and project rostrally on a ventromedial course to the nucleus accumbens and to extrastriatal structures including the pallidum and subthalamus. In contrast, more lateral mDN axons originate within the SN and take a relatively dorsolateral course on their rostral traverse (Figure 1A). Although several factors, including Slit-1 and -2 [3], Netrins [4], Ephrins [5] and Semaphorins [6], have been implicated in mDN pathfinding, the molecular basis of the diversity of mDN axonal projections is unknown.


Sonic hedgehog is a chemoattractant for midbrain dopaminergic axons.

Hammond R, Blaess S, Abeliovich A - PLoS ONE (2009)

Sonic Hedgehog signaling is a candidate guidance cue for mDNs.(A, B) Immunohistochemical analysis of Sonic Hedgehog (Shh) and Smoothened (Smo) expression in relation to the tyrosine hydroxylase (TH)- positive midbrain dopaminergic neurons (mDN) in E12.5 mouse embryos. (A) Shh expression in the ventral midline of the midbrain (mb) ventricular zone (indicated by arrowhead in left panel) lies dorsal to differentiated mDN (TH+). Shh expression in the hypothalamus (hyp) lies ventral and rostral to the dopaminergic cell bodies (indicated by arrow in left panel). Note that TH+ mDN axonal projections are found in the Shh expressing region in the hypothalamus (arrows in right panel). The right panel, a higher magnification of the boxed area in the merged image, is a maximum intensity projection of a Z-stack acquired with the Zeiss ApoTome system. Asterisks in merged image indicate background staining of blood vessels. Aqueduct is outlined. Immunostaining was performed on coronal sections. The plane of section is indicated in schematic in D. (B) Smo expression co-localizes with the midbrain dopaminergic population. Immunostaining was performed on sagittal sections. The area shown is indicated in the schematic in D. (C) Mid-sagittal sections of E12.5 embryonic brain. Arrows indicate location of dopaminergic neurons. The area shown is indicated in the schematic in D. TH/Hoechst: Immunostaining for TH and Hoechst showing the location of dopaminergic neurons (arrow) in relation to the aqueduct (aq) and 3rd ventricle (vt) (outlined) and the mid/hindbrain boundary (MHB). Ptc: Analysis of Ptc-lacZ [18] mice by X-gal staining for β-galactosidase activity shows expression of Patched in the ventral midbrain. Blue staining indicates Ptc-lacZ expression, pink staining is a nuclear stain (nuclear fast red). Smo: In situ hybridization for Smo shows expression of Smo in the ventral midbrain. Shh: In situ hybridization for Shh shows expression dorsal (in mb) and rostral (in hyp) to the mDN cell population. (D) Schematic of sagittal (left panel) and transverse sections (right panels) of midbrain at E12.5. Lateral SN neuronal projections that course to the dorsolateral striatum precursor are in green. Medial ventral projections from the VTA, which project to the nucleus accumbens precursor, are in red. Additional medial fibers project ventrally to the pallidum. Pink line depicts the floor plate and ventral midline. Sagittal schematic: Brown line displays the midbrain-hindbrain junction. Dashed line corresponds to the orientation of the transverse section in A. Black box depicts the sagittal sections in B. Dashed box depict sagittal sections in C. Transverse schematic: Green and red circles in midbrain depict mDN cell bodies, small green and red circles in hypothalamus depict mDN axonal projections. Scale bars: (A) 100 µm (merge) and 20 µm (high mag); (B) 50 µm; (C) 200 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2742719&req=5

pone-0007007-g001: Sonic Hedgehog signaling is a candidate guidance cue for mDNs.(A, B) Immunohistochemical analysis of Sonic Hedgehog (Shh) and Smoothened (Smo) expression in relation to the tyrosine hydroxylase (TH)- positive midbrain dopaminergic neurons (mDN) in E12.5 mouse embryos. (A) Shh expression in the ventral midline of the midbrain (mb) ventricular zone (indicated by arrowhead in left panel) lies dorsal to differentiated mDN (TH+). Shh expression in the hypothalamus (hyp) lies ventral and rostral to the dopaminergic cell bodies (indicated by arrow in left panel). Note that TH+ mDN axonal projections are found in the Shh expressing region in the hypothalamus (arrows in right panel). The right panel, a higher magnification of the boxed area in the merged image, is a maximum intensity projection of a Z-stack acquired with the Zeiss ApoTome system. Asterisks in merged image indicate background staining of blood vessels. Aqueduct is outlined. Immunostaining was performed on coronal sections. The plane of section is indicated in schematic in D. (B) Smo expression co-localizes with the midbrain dopaminergic population. Immunostaining was performed on sagittal sections. The area shown is indicated in the schematic in D. (C) Mid-sagittal sections of E12.5 embryonic brain. Arrows indicate location of dopaminergic neurons. The area shown is indicated in the schematic in D. TH/Hoechst: Immunostaining for TH and Hoechst showing the location of dopaminergic neurons (arrow) in relation to the aqueduct (aq) and 3rd ventricle (vt) (outlined) and the mid/hindbrain boundary (MHB). Ptc: Analysis of Ptc-lacZ [18] mice by X-gal staining for β-galactosidase activity shows expression of Patched in the ventral midbrain. Blue staining indicates Ptc-lacZ expression, pink staining is a nuclear stain (nuclear fast red). Smo: In situ hybridization for Smo shows expression of Smo in the ventral midbrain. Shh: In situ hybridization for Shh shows expression dorsal (in mb) and rostral (in hyp) to the mDN cell population. (D) Schematic of sagittal (left panel) and transverse sections (right panels) of midbrain at E12.5. Lateral SN neuronal projections that course to the dorsolateral striatum precursor are in green. Medial ventral projections from the VTA, which project to the nucleus accumbens precursor, are in red. Additional medial fibers project ventrally to the pallidum. Pink line depicts the floor plate and ventral midline. Sagittal schematic: Brown line displays the midbrain-hindbrain junction. Dashed line corresponds to the orientation of the transverse section in A. Black box depicts the sagittal sections in B. Dashed box depict sagittal sections in C. Transverse schematic: Green and red circles in midbrain depict mDN cell bodies, small green and red circles in hypothalamus depict mDN axonal projections. Scale bars: (A) 100 µm (merge) and 20 µm (high mag); (B) 50 µm; (C) 200 µm.
Mentions: Mammalian mDN axonal projections course rostrally towards forebrain structures that are expanded in both the dorsoventral and mediolateral axes. The most medial and ventral mDN projections, within the VTA, regulate reward-associated behavior and novelty learning and project rostrally on a ventromedial course to the nucleus accumbens and to extrastriatal structures including the pallidum and subthalamus. In contrast, more lateral mDN axons originate within the SN and take a relatively dorsolateral course on their rostral traverse (Figure 1A). Although several factors, including Slit-1 and -2 [3], Netrins [4], Ephrins [5] and Semaphorins [6], have been implicated in mDN pathfinding, the molecular basis of the diversity of mDN axonal projections is unknown.

Bottom Line: Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient.In addition to the role of Shh in the induction of mDN precursors, Shh plays an important role in dopaminergic axon pathfinding to rostral target tissues.Furthermore, Shh signaling is involved in determining the structural diversity of these dopaminergic projections.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Center for Neurobiology and Behavior and Taub Institute, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.

ABSTRACT
Midbrain dopaminergic axons project from the substantia nigra (SN) and the ventral tegmental area (VTA) to rostral target tissues, including the striatum, pallidum, and hypothalamus. The axons from the medially located VTA project primarily to more medial target tissues in the forebrain, whereas the more lateral SN axons project to lateral targets including the dorsolateral striatum. This structural diversity underlies the distinct functions of these pathways. Although a number of guidance cues have been implicated in the formation of the distinct axonal projections of the SN and VTA, the molecular basis of their diversity remains unclear. Here we investigate the molecular basis of structural diversity in mDN axonal projections. We find that Sonic Hedgehog (Shh) is expressed at a choice point in the course of the rostral dopaminergic projections. Furthermore, in midbrain explants, dopaminergic projections are attracted to a Shh source. Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient. In addition to the role of Shh in the induction of mDN precursors, Shh plays an important role in dopaminergic axon pathfinding to rostral target tissues. Furthermore, Shh signaling is involved in determining the structural diversity of these dopaminergic projections.

Show MeSH