scholarly journals Functional Requirements for a Samd14-Capping Protein Complex in Stress Erythropoiesis

2022 ◽  
Author(s):  
Suhita Ray ◽  
Linda Chee ◽  
Yichao Zhou ◽  
Meg A Schaefer ◽  
Michael J Naldrett ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Rapid Expansion ◽  
Functional Requirements ◽  
Erythroid Precursor ◽  
Capping Protein ◽  
Stress Erythropoiesis ◽  
Erythroid Precursors ◽  
Actin Capping Protein ◽  
Stress Dependent ◽  
And Function

Acute anemia induces rapid expansion of erythroid precursors and accelerated differentiation to replenish erythrocytes. Paracrine signals – involving cooperation between SCF/c-Kit signaling and other signaling inputs – are required for the increased erythroid precursor activity in anemia. Our prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene increases the regenerative capacity of the erythroid system and promotes stress-dependent c-Kit signaling. However, the mechanism underlying Samd14’s role in stress erythropoiesis is unknown. We identified a protein-protein interaction between Samd14 and the α- and β heterodimers of the F-actin capping protein (CP) complex. Knockdown of the CP β subunit increased erythroid maturation in ex vivo cultures and decreased colony forming potential of stress erythroid precursors. In a genetic complementation assay for Samd14 activity, our results revealed that the Samd14-CP interaction is a determinant of erythroid precursor cell levels and function. Samd14-CP promotes SCF/c-kit signaling in CD71med spleen erythroid precursors. Given the roles of c-Kit signaling in hematopoiesis and Samd14 in c-Kit pathway activation, this mechanism may have pathological implications in acute/chronic anemia.

scholarly journals The Samd14-Capping Protein Complex Controls Cell Signaling in the Erythropoietic Stress Response

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Kyle J Hewitt
Keyword(s):  
Cell Signaling ◽  
Conflicts Of Interest ◽  
Erythroid Progenitors ◽  
Capping Protein ◽  
Sam Domain ◽  
Stress Erythropoiesis ◽  
Intron 1 ◽  
Actin Capping Protein ◽  
Stress Dependent ◽  
Actin Capping

In anemia, restoring homeostatic levels of erythrocytes requires an erythropoietic regenerative response to accelerate red blood cell (RBC) production. Elucidating mechanisms that drive the process of erythropoiesis in the context of regeneration or "stress erythropoiesis" can reveal new strategies for targeting ineffective erythropoiesis. An important component of stress erythropoiesis involves stress-dependent activation of genes/proteins through transcriptional enhancers. We discovered an enhancer in intron 1 of the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene elevates Samd14 expression, facilitates SCF/c-Kit signaling, and is needed for survival in a hemolytic anemia model. However, it is dispensable for erythropoietic development. Our prior work demonstrated that the SAM domain of Samd14 promotes c-Kit-mediated cellular signaling to regulate progenitor function, and this SAM domain has functional attributes unique from those of structurally related SAM domains. Using immunoprecipitation-mass spectrometry, we determined that Samd14 interacts with the Capzβ protein. Capzβ is a component of the actin capping protein (CP) complex, which interact as α- and β heterodimers during actin filament assembly/disassembly. CP exerts diverse functions in cell motility, vesicular transport, cell signaling and cytokinesis. Using a series of Samd14 deletion constructs, we tested whether the Samd14-Capzβ interaction is important for Samd14 promotion of c-Kit signaling in stress erythroid progenitors. Our findings determined that the region of Samd14 required for binding to Capzβ (amino acids 38-54) were required to restore c-Kit signaling. Our ongoing studies are examining whether Samd14-Capzβ is similarly required for colony formation and cell survival of stress erythroid progenitors, and whether additional SAM domain-containing proteins have a similar role in regulating stress erythropoiesis. Understanding the fundamental drivers of regenerative erythropoiesis can lead to new therapeutic strategies and prognostic/diagnostic markers. Disclosures No relevant conflicts of interest to declare.

scholarly journals Functional Requirements of a Samd14-Capping Protein Interaction in Stress Erythropoiesis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 288-288
Author(s):  
Suhita Ray ◽  
Linda Chee ◽  
Nicholas T. Woods ◽  
Kyle J Hewitt
Keyword(s):  
Steady State ◽  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Interacting Proteins ◽  
Erythroid Progenitors ◽  
Erythroid Progenitor ◽  
Capping Protein ◽  
Sam Domain ◽  
Stress Erythropoiesis

Abstract Stress erythropoiesis describes the process of accelerating red blood cell (RBC) production in anemia. Among a number of important mediators of stress erythropoiesis, paracrine signals - involving cooperation between SCF/c-Kit signaling and other signaling inputs - are required for the activation/function of stress erythroid progenitors. Whereas many critical factors required to drive erythropoiesis in normal physiological conditions have been described, whether distinct mechanisms control developmental, steady-state, and stress erythropoiesis in anemia is poorly understood. Our prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene is transcriptionally upregulated in a model of acute hemolytic anemia induced by the RBC-lysing chemical phenylhydrazine. Samd14 is regulated by GATA binding transcription factors via an intronic enhancer (Samd14-Enh). In a mouse knockout of Samd14-Enh (Samd14-Enh -/-), we established that the Samd14-Enh is dispensable for steady-state erythropoiesis but is required for recovery from severe hemolytic anemia. Samd14 promotes c-Kit signaling in vivo and ex vivo, and the SAM domain of Samd14 facilitates c-Kit-mediated cellular signaling and stress progenitor activity. In addition, the Samd14 SAM domain is functionally distinct from closely related SAM domains, which demonstrates a unique role for this SAM domain in stress signaling and cell survival. In our working model, Samd14-Enh is part of an ensemble of anemia-responsive enhancers which promote stress erythroid progenitor activity. However, the mechanism underlying Samd14's role in stress erythropoiesis is unknown. To identify potential Samd14-interacting proteins that mediate its function, we performed immunoprecipitation-mass spectrometry on the Samd14 protein. We found that Samd14 interacted with α- and β heterodimers of the F-actin capping protein (CP) complex independent of the SAM domain. CP binds to actin during filament assembly/disassembly and plays a role in cell morphology, migration, and signaling. Deleting a 17 amino acid sequence near the N-terminus of Samd14 disrupted the Samd14-CP interaction. However, mutating the canonical RxR of the CP interaction (CPI) motif, which is required for CP-binding in other proteins, does not abrogate the Samd14-CP interaction. Moreover, replacing this sequence with the canonical CPI domain of CKIP-1 completely disrupts the interaction, indicating that other sequence features are required to maintain the Samd14-CP complex. Ex vivo knockdown of the β-subunit of CP (CPβ), which disrupts the integrity of the CP complex, decreased the percentage of early erythroid precursors (p<0.0001) and decreased (3-fold) progenitor activity as measured by colony formation assays (similar to knockdown of Samd14). Taken together, these data indicate that Samd14 interacts with CP via a unique CP binding (CPB) domain, and that the CP complex coordinates erythroid differentiation in stress erythroid progenitors. To test the function of the Samd14-CP complex, we designed an ex vivo genetic complementation assay to express Samd14 lacking the CPB-domain (Samd14∆CPB) in stress erythroid progenitors isolated from anemic Samd14-Enh -/- mice. Phospho-AKT (Ser473) and phospho-ERK (Thr202/Tyr204) levels in Samd14∆CPB were, respectively, 2.2 fold (p=0.007) and ~7 fold (n=3) lower than wild type Samd14 expressing cells, 5 min post SCF stimulation. Relative to Samd14, Samd14∆CPB expression reduced burst forming unit-erythroid (BFU-E) (2.0 fold) and colony forming unit-erythroid (CFU-E) (1.5 fold). These results revealed that the Samd14-CP interaction is a determinant of BFU-E and CFU-E progenitor cell levels and function. Remarkably, as the requirement of the CPB domain in BFU-E and CFU-E progenitors is distinct from the Samd14-SAM domain (which promotes BFU-E but not CFU-E), the function of Samd14 in these two cell types may differ. Ongoing studies will examine whether the function of Samd14 extends beyond SCF/c-Kit signaling and establish cell type-dependent functions of Samd14 and Samd14-interacting proteins. Given the critical importance of c-Kit signaling in hematopoiesis, the role of Samd14 in mediating pathway activation, and our discovery implicating the capping protein complex in erythropoiesis, it is worth considering the pathological implications of this mechanism in acute/chronic anemia and leukemia. Disclosures No relevant conflicts of interest to declare.

Fas-Dependent Apoptosis in Early MDS Erythroid Precursors Involves Endoplasmic Reticulum.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3346-3346
Author(s):  
Emmanuel Gyan ◽  
Emilie Frisan ◽  
Odile Beyne-Rauzy ◽  
Cecile Pierre-Eugene ◽  
Jean-Christophe Deschemin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endoplasmic Reticulum ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Caspase 8 ◽  
Spontaneous Apoptosis ◽  
Cytochrome C Release ◽  
Erythroid Precursor ◽  
Erythroid Precursors

Abstract The anemia that characterizes most early myelodysplastic syndromes (MDS) was proposed to involve a deregulation in cell death pathways leading to excessive apoptosis of bone marrow erythroid precursors. Pathways leading to this excess in MDS erythroid precursors have been partially depicted in ex vivo liquid cultures of patients CD34+ bone marrow cells induced to differentiate into red cells in the presence of various cytokines. For example, we have identified the Fas-dependent activation of caspase-8 as a key initiating event. In order to further understand the mechanisms of MDS erythroid precursor death, we explored the role of the endoplasmic reticulum (ER) in this process. We first observed that Fas-dependent activation of caspase-8 in these cells induced the cleavage of BAP-31, an ER protein that is associated to Bcl-2 at the ER surface and was demonstrated to be a caspase-8 substrate. We also detected a proteolysis of caspase-4, which was proposed to play a role in ER-mediated apoptosis. To further explore the role of the ER, we constructed a lentivirus expressing a Bcl-2 mutant targeted to the ER membrane. The specific expression of Bcl-2 at the ER level prevented BAP-31 and caspase-4 cleavage induced by Fas engagement at the surface of MDS erythroid precursors and inhibited Fas-dependent apoptosis. Interestingly, ER-targeted Bcl-2 also inhibited mitochondrial membrane permeabilization (MMP) and cytochrome c release in MDS erythroid precursors undergoing spontaneous or Fas-induced apoptosis. These data argued for a role of the ER in MDS erythroid precursor apoptosis, upstream of the mitochondria. MDS erythroid precursors also demonstrated elevated ER Ca2+ stores when compared to normal erythroid precursors cultured in the same conditions. Ca2+ chelation with BAPTA or treatment with pharmacologic Ca2+ inhibitors such as nicardipine prevented the spontaneous apoptosis of MDS erythroid precursors. Altogether, these data suggest that the ER is involved in the spontaneous apoptosis of MDS erythroid precursors, downstream of Fas and upstream of the mitochondria, through mechanisms that can be inhibited by Bcl-2 and that involve Ca2+ stores.

scholarly journals ATF4 mediates fetal globin upregulation in response to reduced β-globin

2020 ◽  
Author(s):  
Mandy Boontanrart ◽  
Gautier Stehli ◽  
Marija Banovic ◽  
Markus S. Schröder ◽  
Stacia Wyman ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Time Course ◽  
Cellular Stress ◽  
Erythroid Precursor ◽  
Unfolded Protein ◽  
Stress Erythropoiesis ◽  
Erythroid Precursors ◽  
As Stress ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractFetal development and anemias such as β-hemoglobinopathies trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin, which has suggested strategies to treat hemoglobinopathies such as thalassemia and sickle cell disease. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here we use CRISPR-Cas genome editing and CRISPRi transcriptional repression to model the stress caused by reduced levels of adult β-globin. We find that loss of β-globin is sufficient to induce widespread globin compensation, including robust re-expression of γ-globin. Time-course RNA-seq of differentiating isogenic erythroid precursors identified the ATF4 transcription factor as a causal regulator of this response. ChIP-seq of multiple erythroid precursor genotypes and differentiation states revealed that β-globin knockout leads to reduced engagement of ATF4 targets involved in the unfolded protein response. This ATF4 program indirectly regulates the levels of BCL11A, a key repressor of γ-globin. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could be relevant for proposed gene editing strategies to treat hemoglobinopathies.

scholarly journals The Samd14 Sterile Alpha Motif Domain Promotes Stress-Induced Cellular Signaling and Survival

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1184-1184
Author(s):  
Kyle J Hewitt ◽  
Suhita Ray ◽  
Srinivas Chava ◽  
Linda Chee
Keyword(s):  
Bone Marrow ◽  
Ex Vivo ◽  
Full Length ◽  
Rapid Expansion ◽  
Erythroid Progenitors ◽  
Sterile Alpha Motif ◽  
Erythroid Progenitor ◽  
Erythroid Precursor ◽  
Sam Domain

More than 200 mammalian proteins contain Sterile Alpha Motif (SAM) domains. While some of these domains are reported to mediate protein, lipid or RNA binding, the majority have not been analyzed. Our prior work discovered that Samd14, a SAM-domain containing protein, was transcriptionally activated by the GATA2 and Scl/TAL1-occupied Samd14 enhancer (Samd14-Enh). Deletion of Samd14-Enh lowers Samd14 expression in mouse bone marrow and spleen and causes lethality in a mouse model of severe hemolytic anemia. In anemia, stress erythroid progenitors respond to a multitude of paracrine signals, including erythropoietin (Epo) and stem cell factor (SCF), to induce rapid expansion and differentiation until homeostasis is re-established. Mechanistic analyses revealed that Samd14 regulates SCF/c-Kit signaling, erythroid progenitor function and promotes erythrocyte regeneration in anemia. Ex vivo, Samd14-Enh-/- erythroid progenitors (CD71+Ter119-Kit+) exhibited 2.1-fold and 1.6-fold lower phospho (Serine 473) AKT (pAKT) vs. WT in response to 5 min and 10 min SCF stimulation, respectively. To rigorously establish whether the Samd14-Enh deletion reduces anemia-dependent c-Kit signaling by lowering Samd14 levels in erythroid progenitors, we restored Samd14 expression in Samd14-Enh-/- primary erythroid precursor cells. Defective SCF/c-Kit signaling in Samd14-Enh-/- spleen progenitors could be rescued by reestablishing expression of Samd14. To test the role of the SAM domain in Samd14-mediated promotion of stress-induced erythroid progenitor function, we generated a SAM-domain deleted construct of Samd14 (Samd14 Δ SAM) to replace endogenous expression in cells from Samd14-Enh-deleted bone marrow and spleen ex vivo. In colony assays, full-length Samd14 increased GFP+ colony formation 2.7-fold, whereas there was no significant increase in colonies when expressing Samd14 Δ SAM vs. EV. Compared to expression of full-length Samd14, Samd14 Δ SAM exhibited 1.9-fold fewer (p=0.0006) BFU-E colonies (Figure 4B). Together, these results indicated that the Samd14 SAM domain is required for maximal promotion of colony forming ability, cell signaling and survival of erythroid progenitors. As the Samd14 SAM domain mediates SCF/c-Kit signaling, and cells lacking Samd14-Enh have impaired c-Kit signaling following anemia, this protein motif controls anemia-dependent erythroid progenitor cell genesis and/or function. Ongoing analyses to fuse the SAM structural domains of related proteins Neurabin-1 and SHIP-2 will test the sequence requirements of the Samd14 SAM domain on c-Kit signaling and stress erythroid progenitor function. These findings reveal a vital SAM domain-dependent molecular mechanism in stress erythroid progenitors whereby a GATA2 and anemia-activated protein facilitates SCF/c-Kit signaling during regenerative erythropoiesis. Given the importance of GATA2 and GATA2-dependent mechanisms in hematopoiesis, determining the role of the GATA2-Samd14-c-Kit axis in hematologic diseases may reveal unique functions. Disclosures No relevant conflicts of interest to declare.

Deficiency of Rac1 and Rac2 GTPases Perturbs Erythroid Proliferation and Differentiation but Not Enucleation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 467-467 ◽  
Author(s):  
Theodosia A. Kalfa ◽  
Suvarnamala Pushkaran ◽  
Jose A. Cancelas ◽  
Michael Jansen ◽  
James F. Johnson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Ex Vivo ◽  
Terminal Differentiation ◽  
Fluorescent Label ◽  
Spleen Cells ◽  
Hematopoietic Stem ◽  
Erythroid Precursor ◽  
Survival Difference ◽  
Erythroid Precursors

Abstract The small Rho GTPases Rac1 and Rac2 have overlapping as well as distinct roles in actin organization, cell survival, and proliferation in various hematopoietic cell lineages. However their role in erythropoiesis has not yet been fully elucidated. Using conditional gene-targeted mice we demonstrated that deficiency of Rac1 and Rac2 GTPases causes a significant phenotype in erythroid lineage. The mice develop anemia that is both hemolytic (abnormal structure of the erythrocyte cytoskeleton and decreased deformability; Kalfa et al. Blood 2006) and dyserythropoietic in nature. Cre-recombinase-induced deletion of Rac1 genomic sequence was accomplished as previously described (Gu et al. Science, 2003) on a Rac2-null genetic background. Colony assays revealed that although BFU-E frequency was similar, Rac1−/ −;Rac2−/ − BFU-E colonies had a strikingly different morphology appearing as round, small, dense colonies with solid edges, likely a manifestation of migration defects associated with Rac GTPase deficiency. CFU-E formation from hematopoietic stem/progenitors (HSC/Ps) derived from bone marrow (BM) of Rac1−/ −;Rac2−/ − mice was decreased more than 50% in comparison to WT (p=0.01). On the other hand, Rac1−/ −;Rac2−/ − mice developed marked splenomegaly (2-fold enlargement) and low density spleen cells demonstrated a 2-fold increase in CFU-E frequency in comparison to WT (p=0.008). To further assess erythroblast differentiation, BM and spleen cells were immunostained with fluorescent label-conjugated anti-CD71 and anti-Ter119, as previously described (Socolovski et al. Blood, 2001). Flow cytometry analysis revealed that the BM content of proerythroblasts and basophilic erythroblasts was significantly decreased (>5-fold) in Rac1−/ −;Rac2−/ − vs. WT mice. In contrast, the same erythroblast populations were 4-fold increased in the spleens of Rac1−/ −;Rac2−/ − animals. However, the terminal differentiation to orthochromatic erythroblasts was comparable. No survival difference was found between WT and Rac1−/ −;Rac2−/ − erythroid precursors by flow cytometry with annexin-V, indicating that apoptosis was not contributing to the changes in erythropoiesis in Rac-deficient mice. Differentiation of Rac1−/ −;Rac2−/ − HSC/Ps to proerythroblasts and basophilic erythroblasts was delayed significantly at the early stages in ex vivo erythropoiesis culture (Giarratana et al. Nat Biotechnol, 2005) in the presence of SCF and erythropoietin. Later in the culture the cytokine-independent terminal differentiation to orthochromatic erythroblasts was similar between WT and Rac1−/ −;Rac2−/ − mice. The phosphorylation of AKT in WT and Rac1−/ −;Rac2−/ − erythroid precursors revealed by immunoblotting was similar, but the phosphorylation of extracellular signal-regulated kinase (ERK) (p42/p44) in Rac1−/ −;Rac2−/ − erythroid precursors was significantly decreased. The enucleation process was evaluated quantitatively, in ex vivo erythropoiesis cultures, by flow cytometry, using SYTO16, a cell-permeable DNA-staining dye. The frequency of enucleated red cells (SYTO16-negative, Ter119-positive population) was similar in the WT and Rac1−/ −;Rac2−/ − erythroid cultures. These data suggest that Rac1 and Rac2 deficiency does not affect enucleation but causes a significant decrease of early erythroid precursor populations in the bone marrow.

Extensively Self-Renewing Erythroid Precursors Emerge from the Embryo but Not from the Adult

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2455-2455
Author(s):  
Samantha England ◽  
Kathleen E. McGrath ◽  
James Palis
Keyword(s):  
Fetal Liver ◽  
Globin Gene ◽  
Yolk Sac ◽  
Erythroid Progenitor ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Erythroid Precursor ◽  
Stress Erythropoiesis ◽  
Erythroid Precursors

Abstract The only cell in the hematopoietic hierarchy thought to be capable of long-term selfrenewal is the stem cell. An erythroid progenitor derived from mammalian hematopoietic tissue, fetal or adult, is capable of limited proliferation (103–106 fold expansion; Bauer, 1999; Panzenböck, 1998; von Lindern, 1999). Here we report that an erythroid precursor derived from the mouse embryo is capable not only of limited, but also of extensive proliferation (~1030 fold expansion). These cells resemble proerythroblasts and basophilic erythroblasts based on their morphology, their globin gene expression profile, and their immunophenotype. While aneuploidy is not necessary for extensive proliferation, it sporadically begins to accumulate after prolonged culture. These cells are capable of massive (>100 days) daily proliferation in vitro in the presence of Epo, SCF, IGF-1, and dexamethasone. Examination of cultures lacking each of these factors support that glucocorticoids play an important role in this expansion by uncoupling erythroid precursor proliferation from maturation. Despite prolonged in vitro culture, these cells preserve their potential to fully differentiate into enucleated red blood cells with the removal of dexamethasone. Differentiation occurs over 2–3 days and is characterized by the accumulation of adult (α, β1, and β2), but not embryonic (ζ, εy, and βH1), globins. The retention of full differentiation potential despite >1030 fold expansion indicates that this proliferation represents self-renewal. To determine the developmental origin of these extensively self-renewing erythroblasts (ESREs), we initiated in vitro cultures from staged mouse embryos as well as adult tissues. E7.5 embryos, that contain primitive but not definitive erythroid progenitors, failed to generate ESREs. In contrast, ESREs can be derived from E8.5–E10.5 yolk sac and E11.5–E14.5 fetal liver. These findings along with the globin expression pattern indicate that erythroblast self-renewal is associated with definitive, but not primitive, erythropoiesis. Surprisingly, marrow from adult steady-state hematopoiesis failed to yield ESREs. Furthermore, despite the characteristics shared by stress erythropoiesis (adult spleen) and fetal erythropoiesis (liver), stress erythropoiesis only yielded erythroblasts with limited, and not extensive, self-renewal capacity. This result suggests that extensive self-renewal potential is linked either to the transient yolk sac-derived definitive erythroid lineage or to the fetal hematopoietic microenvironment. We are currently investigating the mechanisms responsible for the extensive self-renewal capacity of such lineage-restricted and mature hematopoietic precursors. Our findings raise the possibility that the expansive cellular output of the erythron within the midgestation mammalian embryo may be regulated, in part, at the level of late stage erythroid precursors.

Structural insights into the regulation of actin capping protein by twinfilin C-terminal tail

2021 ◽  
pp. 166891
Author(s):  
Shuichi Takeda ◽  
Ryotaro Koike ◽  
Ikuko Fujiwara ◽  
Akihiro Narita ◽  
Makoto Miyata ◽  
...  
Keyword(s):  
Capping Protein ◽  
Actin Capping Protein ◽  
Actin Capping ◽  
Structural Insights

scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

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