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Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.

Rakić S, Kanatani S, Hunt D, Faux C, Cariboni A, Chiara F, Khan S, Wansbury O, Howard B, Nakajima K, Nikolić M, Parnavelas JG - Cereb. Cortex (2013)

Bottom Line: Interneuron dysfunction in humans is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism.Some of these disorders are believed to emerge during brain formation, at the time of interneuron specification, migration, and synapse formation.This finding identifies Cdk5 as a crucial signaling factor in cortical interneuron development in mammals.

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Affiliation: Department of Cell and Developmental Biology, University College London, London WC1 6BT, UK.

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Cortical interneurons upregulate Cyt1 expression in the pallium. (A) Schematic of ErbB4, illustrating domains and isoforms of the receptor (modified from Sundvall et al. 2008). JMa isoform, but not JMb, is susceptible to proteolytic cleavage. Cyt1 isoform contains a unique tyrosine residue (Y1056), absent in Cyt2, which serves as a binding site for PI3-kinase. (B, C) RT-PCR. ErbB4 isoform expression in FACS-purified forebrain cells from GAD67GFP mice at the indicated time points. GFPGAD67(+) cells represent GABAergic interneurons. (D) Immunoblots of protein lysates from the MGE, LGE, and Cx of E13.5 mice, showing phosphorylation (p) of ErbB4 on Y1056. ErbB4 and βAct serve as loading controls. (E) Schematic, illustrating upregulation of Cyt1 as early-born interneurons (INs) depart from the subpallium, cross the PSB and enter the pallium. Cyt, cytoplasmic; JM, juxtamembrane; RT, reverse transcriptase; TACE, tumor necrosis factor-α converting enzyme.
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BHT290F2: Cortical interneurons upregulate Cyt1 expression in the pallium. (A) Schematic of ErbB4, illustrating domains and isoforms of the receptor (modified from Sundvall et al. 2008). JMa isoform, but not JMb, is susceptible to proteolytic cleavage. Cyt1 isoform contains a unique tyrosine residue (Y1056), absent in Cyt2, which serves as a binding site for PI3-kinase. (B, C) RT-PCR. ErbB4 isoform expression in FACS-purified forebrain cells from GAD67GFP mice at the indicated time points. GFPGAD67(+) cells represent GABAergic interneurons. (D) Immunoblots of protein lysates from the MGE, LGE, and Cx of E13.5 mice, showing phosphorylation (p) of ErbB4 on Y1056. ErbB4 and βAct serve as loading controls. (E) Schematic, illustrating upregulation of Cyt1 as early-born interneurons (INs) depart from the subpallium, cross the PSB and enter the pallium. Cyt, cytoplasmic; JM, juxtamembrane; RT, reverse transcriptase; TACE, tumor necrosis factor-α converting enzyme.

Mentions: The signaling mechanisms by which ErbB4 exerts its functions in cell migration are only partly understood. Unlike other members of ErbB receptor family, this gene is subject to differential promoter usage and alternative splicing (Junttila et al. 2000; Sundvall et al. 2008). On the one hand, extracellular juxtamembrane (JM) isoforms are either sensitive (JMa) or resistant (JMb) to proteolytic cleavage (Fig. 2A). On the other, cytoplasmic isoforms, Cyt1 and Cyt2, differ by the presence (Cyt1) or absence (Cyt2) of a binding site for PI 3-kinase (tyrosine Y1056; Fig. 2A); the coupling of Cyt1 with PI3-kinase/Akt pathway stimulates chemotaxis (Kainulainen et al. 2000; Gambarotta et al. 2004). Here, we observed temporal and spatial regulation of ErbB4 isoform expression in forebrain interneurons (GFPGAD67(+); Fig. 2B,C). Importantly, GFPGAD67(+) cells in the GE, but not in the Cx, at E13.5, lacked expression of the PI3-kinase-binding/chemotaxis-mediating ErbB4 isoform (Cyt1; Fig. 2C). Accordingly, by using phosphorylation state-specific ab, we found that ErbB4 was significantly phosphorylated on Cyt1-specific Y1056 in the Cx, but not in the lateral (L) GE or MGE (Fig. 2D). Together, these findings suggest that ErbB4/PI3-kinase signaling may be important for migration of interneurons toward and within the Cx (Fig. 2E).Figure 2.


Cdk5 phosphorylation of ErbB4 is required for tangential migration of cortical interneurons.

Rakić S, Kanatani S, Hunt D, Faux C, Cariboni A, Chiara F, Khan S, Wansbury O, Howard B, Nakajima K, Nikolić M, Parnavelas JG - Cereb. Cortex (2013)

Cortical interneurons upregulate Cyt1 expression in the pallium. (A) Schematic of ErbB4, illustrating domains and isoforms of the receptor (modified from Sundvall et al. 2008). JMa isoform, but not JMb, is susceptible to proteolytic cleavage. Cyt1 isoform contains a unique tyrosine residue (Y1056), absent in Cyt2, which serves as a binding site for PI3-kinase. (B, C) RT-PCR. ErbB4 isoform expression in FACS-purified forebrain cells from GAD67GFP mice at the indicated time points. GFPGAD67(+) cells represent GABAergic interneurons. (D) Immunoblots of protein lysates from the MGE, LGE, and Cx of E13.5 mice, showing phosphorylation (p) of ErbB4 on Y1056. ErbB4 and βAct serve as loading controls. (E) Schematic, illustrating upregulation of Cyt1 as early-born interneurons (INs) depart from the subpallium, cross the PSB and enter the pallium. Cyt, cytoplasmic; JM, juxtamembrane; RT, reverse transcriptase; TACE, tumor necrosis factor-α converting enzyme.
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BHT290F2: Cortical interneurons upregulate Cyt1 expression in the pallium. (A) Schematic of ErbB4, illustrating domains and isoforms of the receptor (modified from Sundvall et al. 2008). JMa isoform, but not JMb, is susceptible to proteolytic cleavage. Cyt1 isoform contains a unique tyrosine residue (Y1056), absent in Cyt2, which serves as a binding site for PI3-kinase. (B, C) RT-PCR. ErbB4 isoform expression in FACS-purified forebrain cells from GAD67GFP mice at the indicated time points. GFPGAD67(+) cells represent GABAergic interneurons. (D) Immunoblots of protein lysates from the MGE, LGE, and Cx of E13.5 mice, showing phosphorylation (p) of ErbB4 on Y1056. ErbB4 and βAct serve as loading controls. (E) Schematic, illustrating upregulation of Cyt1 as early-born interneurons (INs) depart from the subpallium, cross the PSB and enter the pallium. Cyt, cytoplasmic; JM, juxtamembrane; RT, reverse transcriptase; TACE, tumor necrosis factor-α converting enzyme.
Mentions: The signaling mechanisms by which ErbB4 exerts its functions in cell migration are only partly understood. Unlike other members of ErbB receptor family, this gene is subject to differential promoter usage and alternative splicing (Junttila et al. 2000; Sundvall et al. 2008). On the one hand, extracellular juxtamembrane (JM) isoforms are either sensitive (JMa) or resistant (JMb) to proteolytic cleavage (Fig. 2A). On the other, cytoplasmic isoforms, Cyt1 and Cyt2, differ by the presence (Cyt1) or absence (Cyt2) of a binding site for PI 3-kinase (tyrosine Y1056; Fig. 2A); the coupling of Cyt1 with PI3-kinase/Akt pathway stimulates chemotaxis (Kainulainen et al. 2000; Gambarotta et al. 2004). Here, we observed temporal and spatial regulation of ErbB4 isoform expression in forebrain interneurons (GFPGAD67(+); Fig. 2B,C). Importantly, GFPGAD67(+) cells in the GE, but not in the Cx, at E13.5, lacked expression of the PI3-kinase-binding/chemotaxis-mediating ErbB4 isoform (Cyt1; Fig. 2C). Accordingly, by using phosphorylation state-specific ab, we found that ErbB4 was significantly phosphorylated on Cyt1-specific Y1056 in the Cx, but not in the lateral (L) GE or MGE (Fig. 2D). Together, these findings suggest that ErbB4/PI3-kinase signaling may be important for migration of interneurons toward and within the Cx (Fig. 2E).Figure 2.

Bottom Line: Interneuron dysfunction in humans is often associated with neurological and psychiatric disorders, such as epilepsy, schizophrenia, and autism.Some of these disorders are believed to emerge during brain formation, at the time of interneuron specification, migration, and synapse formation.This finding identifies Cdk5 as a crucial signaling factor in cortical interneuron development in mammals.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Developmental Biology, University College London, London WC1 6BT, UK.

Show MeSH
Related in: MedlinePlus