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The strength of SMAD1/5 activity determines the mode of stem cell division in the developing spinal cord.

Le Dréau G, Saade M, Gutiérrez-Vallejo I, Martí E - J. Cell Biol. (2014)

Bottom Line: However, the mechanisms controlling such events are not fully understood.Characterizing these three modes of division during interneuron generation in the developing chick spinal cord, we demonstrated that they correlate to different levels of activity of the canonical bone morphogenetic protein effectors SMAD1/5.Together, these results lead us to propose that the strength of SMAD1/5 activity dictates the mode of stem cell division during spinal interneuron generation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Parc Científic de Barcelona, Barcelona 08028, Spain.

ABSTRACT
The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis. However, the mechanisms controlling such events are not fully understood. We have developed markers that provide the single cell resolution necessary to identify the three modes of division occurring in a developing nervous system: self-expanding, self-renewing, and self-consuming. Characterizing these three modes of division during interneuron generation in the developing chick spinal cord, we demonstrated that they correlate to different levels of activity of the canonical bone morphogenetic protein effectors SMAD1/5. Functional in vivo experiments showed that the premature neuronal differentiation and changes in cell cycle parameters caused by SMAD1/5 inhibition were preceded by a reduction of self-expanding divisions in favor of self-consuming divisions. Conversely, SMAD1/5 gain of function promoted self-expanding divisions. Together, these results lead us to propose that the strength of SMAD1/5 activity dictates the mode of stem cell division during spinal interneuron generation.

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Model of the control imposed by SMAD1/5 on the mode of divisions of neural progenitors during spinal interneuron generation. From the onset of spinal interneuron generation, neural progenitors undergo along the dorsal–ventral axis three distinct modes of division: the symmetric proliferative mode (PP, green arrow), which results in the generation of two daughter progenitor cells; the asymmetric mode (PN, yellow arrow), leading to the generation of one daughter progenitor cell while the other daughter cell is committed to differentiate into a neuron; or the symmetric neurogenic (NN, red arrow) mode through which the two daughter cells are committed to differentiation. The decision of a neural progenitor to undergo one division mode or another is under the control of SMAD1/5, so that high, intermediate, and low levels of SMAD1/5 activity dictate neural progenitors to undergo PP, PN, and NN divisions, respectively.
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fig8: Model of the control imposed by SMAD1/5 on the mode of divisions of neural progenitors during spinal interneuron generation. From the onset of spinal interneuron generation, neural progenitors undergo along the dorsal–ventral axis three distinct modes of division: the symmetric proliferative mode (PP, green arrow), which results in the generation of two daughter progenitor cells; the asymmetric mode (PN, yellow arrow), leading to the generation of one daughter progenitor cell while the other daughter cell is committed to differentiate into a neuron; or the symmetric neurogenic (NN, red arrow) mode through which the two daughter cells are committed to differentiation. The decision of a neural progenitor to undergo one division mode or another is under the control of SMAD1/5, so that high, intermediate, and low levels of SMAD1/5 activity dictate neural progenitors to undergo PP, PN, and NN divisions, respectively.

Mentions: Combining newly developed markers that identify the three modes of progenitor division in the developing spinal cord (self-expanding [PP], self-renewing [PN], and self-consuming [NN]) with in vivo manipulations of SMAD1/5 activity, we identified a new role for the canonical BMP effectors SMAD1/5 in dictating the mode of division of neural progenitors during spinal interneuron generation (Fig. 8). Inhibiting SMAD1/5 activity in spinal progenitors at the onset of interneuron generation provoked a premature increase in NN divisions at the expense of PP ones, leading neural progenitors to prematurely exit the cell cycle and undergo differentiation. A consequence of these cell-autonomous effects would be the depletion of the neural progenitor pool, as reflected by the reduction in the size of the VZ containing Sox2+ neural progenitors. This would explain why we ultimately observed a reduction in neuron number after SMAD1/5 inhibition in the developing spinal cord (this study; Le Dréau et al., 2012). A similar mechanism could account for the impaired neurogenesis reported after BMP signaling inhibition during both corticogenesis and dentate development (Segklia et al., 2012; Choe et al., 2013). Accordingly, the canonical BMP signaling thus appears to be crucial for stem cell maintenance both during neural development and adult neurogenesis (Lim et al., 2000; Mira et al., 2010).


The strength of SMAD1/5 activity determines the mode of stem cell division in the developing spinal cord.

Le Dréau G, Saade M, Gutiérrez-Vallejo I, Martí E - J. Cell Biol. (2014)

Model of the control imposed by SMAD1/5 on the mode of divisions of neural progenitors during spinal interneuron generation. From the onset of spinal interneuron generation, neural progenitors undergo along the dorsal–ventral axis three distinct modes of division: the symmetric proliferative mode (PP, green arrow), which results in the generation of two daughter progenitor cells; the asymmetric mode (PN, yellow arrow), leading to the generation of one daughter progenitor cell while the other daughter cell is committed to differentiate into a neuron; or the symmetric neurogenic (NN, red arrow) mode through which the two daughter cells are committed to differentiation. The decision of a neural progenitor to undergo one division mode or another is under the control of SMAD1/5, so that high, intermediate, and low levels of SMAD1/5 activity dictate neural progenitors to undergo PP, PN, and NN divisions, respectively.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3926951&req=5

fig8: Model of the control imposed by SMAD1/5 on the mode of divisions of neural progenitors during spinal interneuron generation. From the onset of spinal interneuron generation, neural progenitors undergo along the dorsal–ventral axis three distinct modes of division: the symmetric proliferative mode (PP, green arrow), which results in the generation of two daughter progenitor cells; the asymmetric mode (PN, yellow arrow), leading to the generation of one daughter progenitor cell while the other daughter cell is committed to differentiate into a neuron; or the symmetric neurogenic (NN, red arrow) mode through which the two daughter cells are committed to differentiation. The decision of a neural progenitor to undergo one division mode or another is under the control of SMAD1/5, so that high, intermediate, and low levels of SMAD1/5 activity dictate neural progenitors to undergo PP, PN, and NN divisions, respectively.
Mentions: Combining newly developed markers that identify the three modes of progenitor division in the developing spinal cord (self-expanding [PP], self-renewing [PN], and self-consuming [NN]) with in vivo manipulations of SMAD1/5 activity, we identified a new role for the canonical BMP effectors SMAD1/5 in dictating the mode of division of neural progenitors during spinal interneuron generation (Fig. 8). Inhibiting SMAD1/5 activity in spinal progenitors at the onset of interneuron generation provoked a premature increase in NN divisions at the expense of PP ones, leading neural progenitors to prematurely exit the cell cycle and undergo differentiation. A consequence of these cell-autonomous effects would be the depletion of the neural progenitor pool, as reflected by the reduction in the size of the VZ containing Sox2+ neural progenitors. This would explain why we ultimately observed a reduction in neuron number after SMAD1/5 inhibition in the developing spinal cord (this study; Le Dréau et al., 2012). A similar mechanism could account for the impaired neurogenesis reported after BMP signaling inhibition during both corticogenesis and dentate development (Segklia et al., 2012; Choe et al., 2013). Accordingly, the canonical BMP signaling thus appears to be crucial for stem cell maintenance both during neural development and adult neurogenesis (Lim et al., 2000; Mira et al., 2010).

Bottom Line: However, the mechanisms controlling such events are not fully understood.Characterizing these three modes of division during interneuron generation in the developing chick spinal cord, we demonstrated that they correlate to different levels of activity of the canonical bone morphogenetic protein effectors SMAD1/5.Together, these results lead us to propose that the strength of SMAD1/5 activity dictates the mode of stem cell division during spinal interneuron generation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Parc Científic de Barcelona, Barcelona 08028, Spain.

ABSTRACT
The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis. However, the mechanisms controlling such events are not fully understood. We have developed markers that provide the single cell resolution necessary to identify the three modes of division occurring in a developing nervous system: self-expanding, self-renewing, and self-consuming. Characterizing these three modes of division during interneuron generation in the developing chick spinal cord, we demonstrated that they correlate to different levels of activity of the canonical bone morphogenetic protein effectors SMAD1/5. Functional in vivo experiments showed that the premature neuronal differentiation and changes in cell cycle parameters caused by SMAD1/5 inhibition were preceded by a reduction of self-expanding divisions in favor of self-consuming divisions. Conversely, SMAD1/5 gain of function promoted self-expanding divisions. Together, these results lead us to propose that the strength of SMAD1/5 activity dictates the mode of stem cell division during spinal interneuron generation.

Show MeSH
Related in: MedlinePlus