43 research outputs found
Structural characterization and statistical-mechanical model of epidermal patterns
In proliferating epithelia of mammalian skin, cells of irregular
polygonal-like shapes pack into complex nearly flat two-dimensional structures
that are pliable to deformations. In this work, we employ various sensitive
correlation functions to quantitatively characterize structural features of
evolving packings of epithelial cells across length scales in mouse skin. We
find that the pair statistics in direct and Fourier spaces of the cell
centroids in the early stages of embryonic development show structural
directional dependence, while in the late stages the patterns tend towards
statistically isotropic states. We construct a minimalist four-component
statistical-mechanical model involving effective isotropic pair interactions
consisting of hard-core repulsion and extra short-ranged soft-core repulsion
beyond the hard core, whose length scale is roughly the same as the hard core.
The model parameters are optimized to match the sample pair statistics in both
direct and Fourier spaces. By doing this, the parameters are biologically
constrained. Our model predicts essentially the same polygonal shape
distribution and size disparity of cells found in experiments as measured by
Voronoi statistics. Moreover, our simulated equilibrium liquid-like
configurations are able to match other nontrivial unconstrained statistics,
which is a testament to the power and novelty of the model. We discuss ways in
which our model might be extended so as to better understand morphogenesis (in
particular the emergence of planar cell polarity), wound-healing, and disease
progression processes in skin, and how it could be applied to the design of
synthetic tissues
Recommended from our members
The cell biology of planar cell polarity
Planar cell polarity (PCP) refers to the coordinated alignment of cell polarity across the tissue plane. Key to the establishment of PCP is asymmetric partitioning of cortical PCP components and intercellular communication to coordinate polarity between neighboring cells. Recent progress has been made toward understanding how protein transport, endocytosis, and intercellular interactions contribute to asymmetric PCP protein localization. Additionally, the functions of gradients and mechanical forces as global cues that bias PCP orientation are beginning to be elucidated. Together, these findings are shedding light on
how global cues integrate with local cell interactions to organize cellular polarity at the tissue level
The role of the dim-1 gene in muscle maintenance and stability in Caenorhabditis elegans
Unc-112 and dim-1 are a pair of interacting genes that are required for myofilament lattice
assembly and maintenance in the nematode, Caenorhabdidtis elegans. The unc-112 gene
encodes a novel protein localized to attachment structures that are responsible for anchoring the
myofilament lattice to the muscle cell membrane and underlying body wall layers. Loss of UNC-
112 results in the failure of myofilament lattice assembly and lethality. Animals homozygous for
the missense mutation unc-112 (r367), on the other hand, survive to adulthood but are paralyzed
and have severely disorganized body wall muscle. Mutations in the dim-1 gene can suppress the
phenotypic defects associated with unc-112 (r367). Animals homozygous for both dim-1 and
unc-112 (r367) display wild type movement and have relatively well organized body wall muscle.
Animals homozygous for the dim-1 mutation alone display mildly disorganized muscle, thus the
dim-1 gene is required for maintaining muscle stability.
The dim-1 gene encodes a 325 amino acid protein that constitutes three immunoglobulin
repeats that are most similar to the intracellular muscle proteins, titin and twitchin.
Immunofluorescence analysis revealed that DIM-1 is expressed in body wall muscle in a pattern
reminiscent of myofilament associated proteins. Preliminary results suggest DIM-1 may
associate with actin containing thin filaments. The disorganized muscle phenotype of dim-1
mutants and the localization of its gene product suggest that DIM-1 maintains the integrity of the
myofilament lattice through the stabilization of thin filaments.
Results presented in this thesis suggest that the suppression of unc-112 (r367) by dim-1 is
indirect. First, sequence alterations for eight dim-1 alleles have been identified all of which result
in the loss of the dim-1 gene product. Thus, the absence of DIM-1 results in the suppression of
unc-112 (r367). Second, DIM-1 is not required for localization of UNC-112 to attachment
structures and third, the DIM-1 protein is localized to myofilaments rather than attachment
structures. These results indicate that the genetic interaction between dim-1 and unc-112 is not
due to a direct interaction between their gene products. Rather, suppression of unc-112 appears
to result from a change in the overall stability of the myofilament lattice caused by the loss of
dim-1. This change may allow the altered r367 protein to maintain the integrity of the
myofilament lattice.Science, Faculty ofZoology, Department ofGraduat
Recommended from our members
Tissue morphodynamics: Translating planar polarity cues into polarized cell behaviors
The ability of cells to collectively orient and align their behaviors is essential in multicellular organisms for unidirectional cilia beating, collective cell movements, oriented cell divisions, and asymmetric cell fate specification. The planar cell polarity pathway coordinates a vast and diverse array of collective cell behaviors by intersecting with downstream pathways that regulate cytoskeletal dynamics and intercellular signaling. How the planar polarity pathway translates directional cues to produce polarized cell behaviors is the focus of this review
Recommended from our members
Planar cell polarity: global inputs establishing cellular asymmetry
Many tissues develop coordinated patterns of cell polarity that align with respect to the tissue axes. This phenomenon refers to planar cell polarity (PCP) and is controlled by multiple conserved PCP modules. A key feature of PCP proteins is their asymmetric localization within the tissue plane, whose orientation is guided by global directional cues. Here, we highlight current models and recent findings on the role of tissue-level gradients, local organizer signals, and mechanical forces in establishing the global patterns of PCP
Recommended from our members
Trans-endocytosis of Planar Cell Polarity Complexes during Cell Division.
To coordinate epithelial architecture with proliferation, cell polarity proteins undergo extensive remodeling during cell division [1-3]. A dramatic example of polarity remodeling occurs in proliferative basal cells of mammalian epidermis whereupon cell division, transmembrane planar cell polarity (PCP) proteins are removed from the cell surface via bulk endocytosis [4]. PCP proteins form intercellular complexes, linked by Celsr1-mediated homophilic adhesion, that coordinate polarity non-autonomously between cells [5, 6]. Thus, the mitotic reorganization of PCP proteins must alter not only proteins intrinsic to the dividing cell but also their interacting partners on neighboring cells. Here, we show that intercellular Celsr1 complexes that connect dividing cells with their neighbors remain intact during mitotic internalization, resulting in an uptake of Celsr1 protein from interphase neighbors. Trans-internalized Celsr1 carries with it additional core PCP proteins, including the posteriorly enriched Fz6 and anteriorly enriched Vangl2. Cadherin-mediated homophilic adhesion is necessary for trans-endocytosis, and adhesive junctional PCP complexes appear to be destined for degradation upon internalization. Surprisingly, whereas Fz6 and Vangl2 both internalize in trans, Vangl2 proteins intrinsic to the dividing cell remain associated with the plasma membrane. Persistent Vangl2 stabilizes Celsr1 and impedes its internalization, suggesting that dissociation of Vangl2 from Celsr1 is a prerequisite for Celsr1 endocytosis. These results demonstrate an unexpected transfer of PCP complexes between neighbors and suggest that the Vangl2 population that persists at the membrane during cell division could serve as an internal cue for establishing PCP in new daughter cells
Recommended from our members
Epithelial geometry regulates spindle orientation and progenitor fate during formation of the mammalian epidermis.
The control of cell fate through oriented cell division is imperative for proper organ development. Basal epidermal progenitor cells divide parallel or perpendicular to the basement membrane to self-renew or produce differentiated stratified layers, but the mechanisms regulating the choice between division orientations are unknown. Using time-lapse imaging to follow divisions and fates of basal progenitors, we find that mouse embryos defective for the planar cell polarity (PCP) gene, Vangl2, exhibit increased perpendicular divisions and hyperthickened epidermis. Surprisingly, this is not due to defective Vangl2 function in the epidermis, but to changes in cell geometry and packing that arise from the open neural tube characteristic of PCP mutants. Through regional variations in epidermal deformation and physical manipulations, we show that local tissue architecture, rather than cortical PCP cues, regulates the decision between symmetric and stratifying divisions, allowing flexibility for basal cells to adapt to the needs of the developing tissue
Recommended from our members
Counter-rotational cell flows drive morphological and cell fate asymmetries in mammalian hair follicles.
Organ morphogenesis is a complex process coordinated by cell specification, epithelial-mesenchymal interactions and tissue polarity. A striking example is the pattern of regularly spaced, globally aligned mammalian hair follicles, which emerges through epidermal-dermal signaling and planar polarized morphogenesis. Here, using live-imaging, we discover that developing hair follicles polarize through dramatic cell rearrangements organized in a counter-rotational pattern of cell flows. Upon hair placode induction, Shh signaling specifies a radial pattern of progenitor fates that, together with planar cell polarity, induce counter-rotational rearrangements through myosin and ROCK-dependent polarized neighbour exchanges. Importantly, these cell rearrangements also establish cell fate asymmetry by repositioning radial progenitors along the anterior-posterior axis. These movements concurrently displace associated mesenchymal cells, which then signal asymmetrically to maintain polarized cell fates. Our results demonstrate how spatial patterning and tissue polarity generate an unexpected collective cell behaviour that in turn, establishes both morphological and cell fate asymmetry
Recommended from our members
Planar cell polarity-dependent and independent functions in the emergence of tissue-scale hair follicle patterns
Hair follicles of the mammalian epidermis display local order and global alignment, a complex
pattern instructed by the core planar cell polarity (PCP) pathway. Here we address the contributions of core PCP genes, Van Gogh-like and Frizzled, to the establishment, local refinement, and global order of embryonic and postnatal hair follicles. We find that, similar to Fz6 mutants, the disordered hair patterns of Vangl2 mutants are refined over time and eventually corrected. In both mutants, we find that tissue-level reorientation occurs through locally coordinated follicle rotation at stereotyped locations. Strikingly, Vangl2 and Fz6 mutant follicles collectively rotate with opposing directionalities, suggesting that redundant core PCP signals contribute to their directed realignment. Consistently, global follicle alignment is not restored upon
conditional ablation of both Vangl1 and Vangl2 genes. Instead, spatially distinct patterns of whorls and crosses emerge and persist even after a complete cycle of hair follicle regeneration. Thus, local refinement of hair follicles into higher order patterns can occur independently of the core PCP system, however, their global alignment with the body axes requires PCP function throughout morphogenesis, growth and regeneration