Figure 1. Disruption of pericentrin function could contribute to human disease through multiple mechanisms. Models for the role of pericentrin in primordial dwarfism. Model I: PCNT disruption leads to centrosome defects including loss of centrosomal Chk1. This perturbs G2/M checkpoint activation in the presence of DNA damage (red X), allowing cells to enter mitosis with damaged DNA and leading to mitotic arrest or cell death. Model II: Centrosome defects such as loss of γ-tubulin compromise microtubule nucleation/organization, leading to spindle defects and, consequently, mitotic arrest or cell death. Model III: Defects in microtubule nucleation/organization disrupt astral microtubules, thus randomizing spindle orientation. This favors asymmetric divisions (Asym. Div, red arrow) and reduces symmetric stem cell self-renewing divisions (S. Div, symmetric division), leading to reduced stem cell number. All models would lead to a decrease in the overall cellularity of tissues. Diff, differentiated cell. Model for the role of pericentrin in cancer progression. Centrosome and associated microtubule defects give rise to disorganized spindles (e.g., multipolar). The resulting aberrant cell divisions cause chromosome losses and gains (aneuploidy), which could lead to accumulation of activated oncogenes and loss of tumor suppressors in daughter cells and thus contribute to cancer progression. Models for the role of pericentrin in mental disorders. Model I: Disruption of centrosome and associated microtubules (red X) perturbs neurite outgrowth and neuronal circuitry. Model II: Disruption of centrosome-mediated microtubule organization leads to defects in cell migration along radial glia (red X). VZ, ventricular proliferative zone. Model III: Disruption of centrosome-mediated astral microtubules depletes neuronal stem cells as described in model III for primordial dwarfism (red arrow). In all models, disruption of brain structure and neurite outgrowth, connectivity, or function would contribute to mental disorders. Models for the role of pericentrin in ciliopathies. Model I: Centrosome disruption, including mislocalization of centrosome proteins and proteins involved in cilia formation, disrupts cilia assembly (red X), leading to ciliopathy-associated phenotypes. Model II: Disruption of centrosome-associated astral microtubules causes randomization of spindle orientation (red arrow), leading to a decrease in cell divisions along the longitudinal axis of the duct (e.g., kidney). This results the expansion of the diameter of the duct, potentially contributing to cyst formation in ciliopathies.
Figure 1.

Disruption of pericentrin function could contribute to human disease through multiple mechanisms. Models for the role of pericentrin in primordial dwarfism. Model I: PCNT disruption leads to centrosome defects including loss of centrosomal Chk1. This perturbs G2/M checkpoint activation in the presence of DNA damage (red X), allowing cells to enter mitosis with damaged DNA and leading to mitotic arrest or cell death. Model II: Centrosome defects such as loss of γ-tubulin compromise microtubule nucleation/organization, leading to spindle defects and, consequently, mitotic arrest or cell death. Model III: Defects in microtubule nucleation/organization disrupt astral microtubules, thus randomizing spindle orientation. This favors asymmetric divisions (Asym. Div, red arrow) and reduces symmetric stem cell self-renewing divisions (S. Div, symmetric division), leading to reduced stem cell number. All models would lead to a decrease in the overall cellularity of tissues. Diff, differentiated cell. Model for the role of pericentrin in cancer progression. Centrosome and associated microtubule defects give rise to disorganized spindles (e.g., multipolar). The resulting aberrant cell divisions cause chromosome losses and gains (aneuploidy), which could lead to accumulation of activated oncogenes and loss of tumor suppressors in daughter cells and thus contribute to cancer progression. Models for the role of pericentrin in mental disorders. Model I: Disruption of centrosome and associated microtubules (red X) perturbs neurite outgrowth and neuronal circuitry. Model II: Disruption of centrosome-mediated microtubule organization leads to defects in cell migration along radial glia (red X). VZ, ventricular proliferative zone. Model III: Disruption of centrosome-mediated astral microtubules depletes neuronal stem cells as described in model III for primordial dwarfism (red arrow). In all models, disruption of brain structure and neurite outgrowth, connectivity, or function would contribute to mental disorders. Models for the role of pericentrin in ciliopathies. Model I: Centrosome disruption, including mislocalization of centrosome proteins and proteins involved in cilia formation, disrupts cilia assembly (red X), leading to ciliopathy-associated phenotypes. Model II: Disruption of centrosome-associated astral microtubules causes randomization of spindle orientation (red arrow), leading to a decrease in cell divisions along the longitudinal axis of the duct (e.g., kidney). This results the expansion of the diameter of the duct, potentially contributing to cyst formation in ciliopathies.

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