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A computational clonal analysis of the developing mouse limb bud.

Marcon L, Arqués CG, Torres MS, Sharpe J - PLoS Comput. Biol. (2011)

Bottom Line: However, disentangling the cumulative effects of the multiple events responsible for the expansion of the labeled cell population is not always straightforward.Our computational analysis produces for the first time a two dimensional model of limb growth based on experimental data that can be used to better characterize limb tissue movement in space and time.The model shows that the distribution and shapes of clones can be described as a combination of anisotropic growth with isotropic cell mixing, without the need for lineage compartmentalization along the AP and PD axis.

View Article: PubMed Central - PubMed

Affiliation: EMBL-CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain. luciano.marcon@crg.es

ABSTRACT
A comprehensive spatio-temporal description of the tissue movements underlying organogenesis would be an extremely useful resource to developmental biology. Clonal analysis and fate mappings are popular experiments to study tissue movement during morphogenesis. Such experiments allow cell populations to be labeled at an early stage of development and to follow their spatial evolution over time. However, disentangling the cumulative effects of the multiple events responsible for the expansion of the labeled cell population is not always straightforward. To overcome this problem, we develop a novel computational method that combines accurate quantification of 2D limb bud morphologies and growth modeling to analyze mouse clonal data of early limb development. Firstly, we explore various tissue movements that match experimental limb bud shape changes. Secondly, by comparing computational clones with newly generated mouse clonal data we are able to choose and characterize the tissue movement map that better matches experimental data. Our computational analysis produces for the first time a two dimensional model of limb growth based on experimental data that can be used to better characterize limb tissue movement in space and time. The model shows that the distribution and shapes of clones can be described as a combination of anisotropic growth with isotropic cell mixing, without the need for lineage compartmentalization along the AP and PD axis. Lastly, we show that this comprehensive description can be used to reassess spatio-temporal gene regulations taking tissue movement into account and to investigate PD patterning hypothesis.

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PD segments progenitors.(A) A reverse tissue movement map was calculated in order to identify the progenitor regions for the three PD segments. In the graphs, the stylopod is highlighted in red, the zeugopod in green and the autopod in blue. (B) On the top, the initial position of the three PD segments is specified as shown by an in situ hybridization at stage E12 of the Sox9 skeletal marker, on the bottom. (C) Graphs showing the retrospective probability to belong to the three segments along the proximal distal axis. The regions having a high probability to belong to more than one segment are highlighted with diagonal black lines.
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pcbi-1001071-g009: PD segments progenitors.(A) A reverse tissue movement map was calculated in order to identify the progenitor regions for the three PD segments. In the graphs, the stylopod is highlighted in red, the zeugopod in green and the autopod in blue. (B) On the top, the initial position of the three PD segments is specified as shown by an in situ hybridization at stage E12 of the Sox9 skeletal marker, on the bottom. (C) Graphs showing the retrospective probability to belong to the three segments along the proximal distal axis. The regions having a high probability to belong to more than one segment are highlighted with diagonal black lines.

Mentions: The positions of the PD segments at E12 were determined by the expression of the Sox9 skeletal marker, see Figure 9B. Based on the degree of cell mixing seen in real clones, our reverse model revealed the existence of regions having high probability to contribute to two or three segments at early stages of development (around stage E10 in Figure 9C) when most of the fate maps discussed above have been performed. In other words, assuming a spatially-uniform cell mixing that matches the observed overlaps of experimental clones, our model clearly suggests that the degree of mixing between the three PD segments does not allow an early specification of the PD identities even as late as E10.


A computational clonal analysis of the developing mouse limb bud.

Marcon L, Arqués CG, Torres MS, Sharpe J - PLoS Comput. Biol. (2011)

PD segments progenitors.(A) A reverse tissue movement map was calculated in order to identify the progenitor regions for the three PD segments. In the graphs, the stylopod is highlighted in red, the zeugopod in green and the autopod in blue. (B) On the top, the initial position of the three PD segments is specified as shown by an in situ hybridization at stage E12 of the Sox9 skeletal marker, on the bottom. (C) Graphs showing the retrospective probability to belong to the three segments along the proximal distal axis. The regions having a high probability to belong to more than one segment are highlighted with diagonal black lines.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037386&req=5

pcbi-1001071-g009: PD segments progenitors.(A) A reverse tissue movement map was calculated in order to identify the progenitor regions for the three PD segments. In the graphs, the stylopod is highlighted in red, the zeugopod in green and the autopod in blue. (B) On the top, the initial position of the three PD segments is specified as shown by an in situ hybridization at stage E12 of the Sox9 skeletal marker, on the bottom. (C) Graphs showing the retrospective probability to belong to the three segments along the proximal distal axis. The regions having a high probability to belong to more than one segment are highlighted with diagonal black lines.
Mentions: The positions of the PD segments at E12 were determined by the expression of the Sox9 skeletal marker, see Figure 9B. Based on the degree of cell mixing seen in real clones, our reverse model revealed the existence of regions having high probability to contribute to two or three segments at early stages of development (around stage E10 in Figure 9C) when most of the fate maps discussed above have been performed. In other words, assuming a spatially-uniform cell mixing that matches the observed overlaps of experimental clones, our model clearly suggests that the degree of mixing between the three PD segments does not allow an early specification of the PD identities even as late as E10.

Bottom Line: However, disentangling the cumulative effects of the multiple events responsible for the expansion of the labeled cell population is not always straightforward.Our computational analysis produces for the first time a two dimensional model of limb growth based on experimental data that can be used to better characterize limb tissue movement in space and time.The model shows that the distribution and shapes of clones can be described as a combination of anisotropic growth with isotropic cell mixing, without the need for lineage compartmentalization along the AP and PD axis.

View Article: PubMed Central - PubMed

Affiliation: EMBL-CRG Systems Biology Research Unit, Center for Genomic Regulation (CRG), Universitat Pompeu Fabra, Barcelona, Spain. luciano.marcon@crg.es

ABSTRACT
A comprehensive spatio-temporal description of the tissue movements underlying organogenesis would be an extremely useful resource to developmental biology. Clonal analysis and fate mappings are popular experiments to study tissue movement during morphogenesis. Such experiments allow cell populations to be labeled at an early stage of development and to follow their spatial evolution over time. However, disentangling the cumulative effects of the multiple events responsible for the expansion of the labeled cell population is not always straightforward. To overcome this problem, we develop a novel computational method that combines accurate quantification of 2D limb bud morphologies and growth modeling to analyze mouse clonal data of early limb development. Firstly, we explore various tissue movements that match experimental limb bud shape changes. Secondly, by comparing computational clones with newly generated mouse clonal data we are able to choose and characterize the tissue movement map that better matches experimental data. Our computational analysis produces for the first time a two dimensional model of limb growth based on experimental data that can be used to better characterize limb tissue movement in space and time. The model shows that the distribution and shapes of clones can be described as a combination of anisotropic growth with isotropic cell mixing, without the need for lineage compartmentalization along the AP and PD axis. Lastly, we show that this comprehensive description can be used to reassess spatio-temporal gene regulations taking tissue movement into account and to investigate PD patterning hypothesis.

Show MeSH