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Adapting for endocytosis: roles for endocytic sorting adaptors in directing neural development.

Yap CC, Winckler B - Front Cell Neurosci (2015)

Bottom Line: The levels of these receptors on the surface and their precise locations can greatly affect guidance outcomes.We will discuss the cell biology of regulated endocytosis and the impact on neural development.We focus our discussion on endocytic accessory proteins (EAPs) (such as numb and disabled) and how they regulate endocytosis and subsequent post-endocytic trafficking of their cognate receptors (such as Notch, TrkB, β-APP, VLDLR, and ApoER2).

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Virginia Charlottesville, VA, USA.

ABSTRACT
Proper cortical development depends on the orchestrated actions of a multitude of guidance receptors and adhesion molecules and their downstream signaling. The levels of these receptors on the surface and their precise locations can greatly affect guidance outcomes. Trafficking of receptors to a particular surface locale and removal by endocytosis thus feed crucially into the final guidance outcomes. In addition, endocytosis of receptors can affect downstream signaling (both quantitatively and qualitatively) and regulated endocytosis of guidance receptors is thus an important component of ensuring proper neural development. We will discuss the cell biology of regulated endocytosis and the impact on neural development. We focus our discussion on endocytic accessory proteins (EAPs) (such as numb and disabled) and how they regulate endocytosis and subsequent post-endocytic trafficking of their cognate receptors (such as Notch, TrkB, β-APP, VLDLR, and ApoER2).

No MeSH data available.


Related in: MedlinePlus

Roles of numb in polarizing signaling responses downstream of BDNF in migrating granule cell precursors (GCPs) in cerebellar development. Polarized distribution of numb at the leading process of a migrating GCP creates a positive feed-forward loop for directional migration. The following steps are proposed (based on Zhou et al., 2011). (1) Higher BDNF in front of migrating GCP. (2) Higher activation of TrkB. (3) Higher recruitment of numb. (4) Higher recruitment of downstream effectors, such as aPKC. (5) Higher numb leads to higher TrkB-P endocytosis via clathrin/AP-2. (6) Higher TrkB endocytosis leads to more TrkB-P in endosomes. (7) More TrkB-P in endosomes recruits more signaling effectors to endosomes. (8) Higher activation of Tiam and Rac to promote more actin assembly in front of cell. (9) Higher signaling promotes preferential recycling of TrkB back to surface at front. (10) TrkB distribution becomes more polarized near front.
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Figure 3: Roles of numb in polarizing signaling responses downstream of BDNF in migrating granule cell precursors (GCPs) in cerebellar development. Polarized distribution of numb at the leading process of a migrating GCP creates a positive feed-forward loop for directional migration. The following steps are proposed (based on Zhou et al., 2011). (1) Higher BDNF in front of migrating GCP. (2) Higher activation of TrkB. (3) Higher recruitment of numb. (4) Higher recruitment of downstream effectors, such as aPKC. (5) Higher numb leads to higher TrkB-P endocytosis via clathrin/AP-2. (6) Higher TrkB endocytosis leads to more TrkB-P in endosomes. (7) More TrkB-P in endosomes recruits more signaling effectors to endosomes. (8) Higher activation of Tiam and Rac to promote more actin assembly in front of cell. (9) Higher signaling promotes preferential recycling of TrkB back to surface at front. (10) TrkB distribution becomes more polarized near front.

Mentions: How is endocytosis of activated TrkB and the subsequent signaling from signaling endosomes regulated in time and space? Numb is an endocytic co-adaptor for activated TrkB (Figure 2): Numb colocalizes with α-adaptin and TrkB in the leading processes, it interacts with the NPXY motif on TrkB after activation (via the numb PTB domain), and it promotes TrkB endocytosis and polarized localization to the leading process of migrating GCPs. Depletion of Numb either by shRNA or conditional knockout impairs BDNF-induced TrkB endocytosis and polarized localization of TrkB to leading processes of migrating GCPs. The polarized localization of numb leads to enhanced endocytosis of activated TrkB at the leading process, increased generation and accumulation of signaling endosomes locally in the leading process of GCPs, and consequently increased activation of downstream signaling cascades that promote local membrane trafficking (such as increased BDNF exocytosis) and cytoskeletal rearrangements that drive directional protrusions and mobility (Zhou et al., 2011; see Figure 3).


Adapting for endocytosis: roles for endocytic sorting adaptors in directing neural development.

Yap CC, Winckler B - Front Cell Neurosci (2015)

Roles of numb in polarizing signaling responses downstream of BDNF in migrating granule cell precursors (GCPs) in cerebellar development. Polarized distribution of numb at the leading process of a migrating GCP creates a positive feed-forward loop for directional migration. The following steps are proposed (based on Zhou et al., 2011). (1) Higher BDNF in front of migrating GCP. (2) Higher activation of TrkB. (3) Higher recruitment of numb. (4) Higher recruitment of downstream effectors, such as aPKC. (5) Higher numb leads to higher TrkB-P endocytosis via clathrin/AP-2. (6) Higher TrkB endocytosis leads to more TrkB-P in endosomes. (7) More TrkB-P in endosomes recruits more signaling effectors to endosomes. (8) Higher activation of Tiam and Rac to promote more actin assembly in front of cell. (9) Higher signaling promotes preferential recycling of TrkB back to surface at front. (10) TrkB distribution becomes more polarized near front.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389405&req=5

Figure 3: Roles of numb in polarizing signaling responses downstream of BDNF in migrating granule cell precursors (GCPs) in cerebellar development. Polarized distribution of numb at the leading process of a migrating GCP creates a positive feed-forward loop for directional migration. The following steps are proposed (based on Zhou et al., 2011). (1) Higher BDNF in front of migrating GCP. (2) Higher activation of TrkB. (3) Higher recruitment of numb. (4) Higher recruitment of downstream effectors, such as aPKC. (5) Higher numb leads to higher TrkB-P endocytosis via clathrin/AP-2. (6) Higher TrkB endocytosis leads to more TrkB-P in endosomes. (7) More TrkB-P in endosomes recruits more signaling effectors to endosomes. (8) Higher activation of Tiam and Rac to promote more actin assembly in front of cell. (9) Higher signaling promotes preferential recycling of TrkB back to surface at front. (10) TrkB distribution becomes more polarized near front.
Mentions: How is endocytosis of activated TrkB and the subsequent signaling from signaling endosomes regulated in time and space? Numb is an endocytic co-adaptor for activated TrkB (Figure 2): Numb colocalizes with α-adaptin and TrkB in the leading processes, it interacts with the NPXY motif on TrkB after activation (via the numb PTB domain), and it promotes TrkB endocytosis and polarized localization to the leading process of migrating GCPs. Depletion of Numb either by shRNA or conditional knockout impairs BDNF-induced TrkB endocytosis and polarized localization of TrkB to leading processes of migrating GCPs. The polarized localization of numb leads to enhanced endocytosis of activated TrkB at the leading process, increased generation and accumulation of signaling endosomes locally in the leading process of GCPs, and consequently increased activation of downstream signaling cascades that promote local membrane trafficking (such as increased BDNF exocytosis) and cytoskeletal rearrangements that drive directional protrusions and mobility (Zhou et al., 2011; see Figure 3).

Bottom Line: The levels of these receptors on the surface and their precise locations can greatly affect guidance outcomes.We will discuss the cell biology of regulated endocytosis and the impact on neural development.We focus our discussion on endocytic accessory proteins (EAPs) (such as numb and disabled) and how they regulate endocytosis and subsequent post-endocytic trafficking of their cognate receptors (such as Notch, TrkB, β-APP, VLDLR, and ApoER2).

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Virginia Charlottesville, VA, USA.

ABSTRACT
Proper cortical development depends on the orchestrated actions of a multitude of guidance receptors and adhesion molecules and their downstream signaling. The levels of these receptors on the surface and their precise locations can greatly affect guidance outcomes. Trafficking of receptors to a particular surface locale and removal by endocytosis thus feed crucially into the final guidance outcomes. In addition, endocytosis of receptors can affect downstream signaling (both quantitatively and qualitatively) and regulated endocytosis of guidance receptors is thus an important component of ensuring proper neural development. We will discuss the cell biology of regulated endocytosis and the impact on neural development. We focus our discussion on endocytic accessory proteins (EAPs) (such as numb and disabled) and how they regulate endocytosis and subsequent post-endocytic trafficking of their cognate receptors (such as Notch, TrkB, β-APP, VLDLR, and ApoER2).

No MeSH data available.


Related in: MedlinePlus