Khalil Mazouni's research while affiliated with Institut Pasteur and other places

Publications (36)

Article
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Multiscale analysis of morphogenesis requires to follow and measure in real-time the in vivo behaviour of large numbers of individual cells over long period of time. Despite recent progress, the large-scale automated tracking of cells in developing embryos and tissues remains a challenge. Here we describe a genetic tool for the random and sparse la...
Article
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The stereotyped arrangement of sensory bristles on the adult fly thorax arises from a self-organized process, in which inhibitory Notch signaling both delimits proneural stripes and singles out sensory organ precursor cells (SOPs). A dynamic balance between proneural factors and Enhancer of split-HLH (E(spl)-HLH) Notch targets underlies patterning,...
Article
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Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralize...
Article
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In epithelia, mitotic cells round up and push against their neighbors to divide. Mitotic rounding results from increased assembly of F-actin and cortical recruitment of Myosin II, leading to increased cortical stability. Whether this process is developmentally regulated is not well known. Here, we examined the regulation of cortical stability in Se...
Article
Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life. In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division. How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly un...
Article
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Crumbs (Crb) is a conserved determinant of apical membrane identity that regulates epithelial morphogenesis in many developmental contexts. In this study, we identify the Crb complex protein Stardust (Sdt) as a target of the E3 ubiquitin ligase Neuralized (Neur) in Drosophila melanogaster . Neur interacts with and down-regulates specific Sdt isofor...
Article
Self-organization for sensory brushes Sensory hairs on the back of a fruit fly are lined up in neat rows. The orderliness of this arrangement has encouraged models based on organized specification of the hairs. Corson et al. now show that development is both less precise and more effective than that. They used mathematical modeling to recapitulate...
Data
Extended Experimental Procedures and Supplemental References. (DOCX)
Article
Full-text available
Author Communication between cells is critical for controlling proliferation, and the Notch signal transduction pathway plays a well-established and evolutionary conserved role during these processes. However, in spite of numerous studies of this pathway over the years, the genetic sensitivity of the pathway, combined with complexity in the nuclea...
Data
(Related to Fig 5) Stg expression levels and number of cells in NB5-6T are both reduced by E(spl)HLHm8CK2 misexpression. (A) Expression of m8CK2, driven by pros-Gal4, results in significantly reduced cell numbers in the NB5-6T lineage (* p≤0.05, ** p≤0.01, *** p≤0.001; +/-SD; Student’s two-tailed T-test; n≥ 24 lineages). (B) Expression of m8CK2, dr...
Data
(Related to Fig 1) Notch controls the Type I>0 switch in NB5-6T. (A-E) The last-born cells in the NB5-6T lineage, the Ap neurons, are born as Type 0 cells; 4 cells in T2-T3 and 5 cells in T1; identifiable by Eya, and neuropeptides FMRFa and Nplp1. (B) kuze29-4, elav>Su(H)RNAi (C), and (D) insc>Tom;neurDf/+, frequently displayed extra Eya cells, as...
Data
(Related to Fig 3) Eya cell numbers in Notch/E(spl) mutants. (A) Quantification of Eya cells in NB5-6T. The three TILLING alleles identified for m5 do not show significant effects when crossed to each other. This is in contrast to the results found when these m5 alleles are placed over a deletion uncovering all seven E(spl)-HLH genes (Df(3R)BSC751)...
Data
DNA sequences of the synthetic Su(H) and E(spl)m8-HLH constructs. (PDF)
Data
(Related to Fig 3) E(spl) TILLING mutations. Primer pairs and PCR fragment size used for the TILLING of the seven E(spl)-HLH genes. The mutated nucleotide and corresponding amino acid mutation is also shown, as well as the stock numbers from the Stowers collection and the Bloomington stock numbers. (PDF)
Data
(Related to Fig 4) Notch does not control the Type I>0 switch via regulation of proneural genes. Previous studies of Notch signaling during the process of lateral inhibition demonstrated that key targets are the genes of the proneural family of bHLH transcription factors; achaete, scute and lethal-of-scute [34, 35]. Addressing the possible role of...
Data
(Related to Fig 3) Genetic redundancy in the E(spl) complex. To begin addressing the role of each member of the E(spl) complex with respect to the Type I>0 switch, we first analyzed a number of deficiencies in this region, using the NB5-6T lineage and the four Ap neurons (Type 0) as readout. As anticipated, these studies revealed a complex picture...
Data
(Related to Fig 5) Activated Notch reduces daughter proliferation. (A) Quantification of the number of NB3-3A cells, at St17 (eg-Gal4/UAS-GFP). While dap or kuz heterozygotes do not show significant increase in NB3-3A lineage cells, kuz/dap transheterozygotes show clear effects. These effects are similar to those observed in kuz or dap homozygotes...
Data
(Related to Fig 5) Generation of stabilized UAS-m8 transgenes. (A) New UAS-m8 constructs were generated, omitting the 5´and 3´UTR, and codon optimizing the ORF for m8. The sequence upstream the start-ATG was altered to match the Drosophila consensus and the CK2 phospho-degron was mutated. The transgene was inserted at 28E on chromosome 2. (B-G) Con...
Data
(Related to Fig 6) ChIP and DamID analysis of Su(H), m5 and m8 reveals binding to Cyclin E and string. (A-B) Normalized binding profiles for ChIP of FLAG-tagged Su(H) and m8CK2, driven by pros-Gal4, as well as DamID, driven by pros-Gal4 or “un-driven”, for m5 and m8. Depicted are the CycE and stg genes. (A) Several peaks were identified on the CycE...
Article
Full-text available
During development, cell-fate diversity can result from the unequal segregation of fate determinants at mitosis [1]. Polarization of the mother cell is essential for asymmetric cell division (ACD). It often involves the formation of a cortical domain containing the PAR complex proteins Par3, Par6, and atypical protein kinase C (aPKC) [1-5]. In the...
Article
Full-text available
Cell fate determination depends in part on the establishment of specific transcriptional programs of gene expression. These programs result from the interpretation of the genomic cis-regulatory information by sequence-specific factors. Decoding this information in sequenced genomes is an important issue. Here, we developed statistical analysis tool...

Citations

... ppn (papilin) encodes a components of the extracellular matrix (ECM) (Campbell et al, 1987) that is, as is most embryonic ECM, expressed by hemocytes during their embryonic migration and its expression therefore did not colocalise with fkh mRNA (Fig. 2 F, F'). E(spl) gene expression dominates one cluster (Couturier et al, 2019;Schrons et al, 1992), and analysis of a GFP trap in E(spl)mg revealed protein expression across the epidermis but excluded from the salivary gland placode marked by fkh mRNA (Fig. 2 G, G'). ...
... Twist both activates Fog and T48 and delays mesoderm cell division until after invagination via expression of the cell cycle inhibitor, Tribbles (Grosshans and Wieschaus, 2000;Seher and Leptin, 2000). Snail promotes apical myosin II recruitment and cell shape change, in part, by repressing the Bearded family of genes (Perez-Mockus et al., 2017). Mist expression is regulated by Snail, and modulated by Twist and Dorsal, while Smog is maternally deposited into the embryo (Manning et al., 2013;Kerridge et al., 2016;Carmon et al., 2021). ...
... As in other mitotic systems 16,17 , Actin is recruited to the SOP cortex at metaphase onset (Extended Data Fig. 1d) during the mitotic rounding process [18][19][20] . In contrast, in late anaphase, the posterior Actin cortex is enriched by fourfold (Fig. 1f,g, Supplementary Video 1 and Extended Data Fig. 1d-h) and is 40% thicker compared with the anterior cortex (Extended Data Fig. 1i,j). ...
... In Xenopus gastrula embryos, after asymmetric cleavage furrowing completes and the midbody is established, new tri-cellular tight junctions are formed basal to and on either end of the MB [59]. In Drosophila sensory organ precursor cell divisions, the new apical junction forms prior to abscission near the midbody [60]. In Drosophila ovary follicular epithelium, when apical junction proteins were experimentally mislocalized on baso-lateral membrane, midbodies formed more basally and epithelial invaginations were observed [61]. ...
... The reason for this prominent shift from MPC to PAC fate is presently unknown, but it was speculated that onset of Lunatic fringe expression around E14.5 in the distal part of the epithelium 43 might play a role. On a larger perspective, beyond the Notch-Delta system, then cell fate choices are sometimes found to be dependent on cell-intrinsic feedback 5,[44][45][46][47] . However, within paradigms that are governed by Notch-Delta systems, our model suggests a dependence on the cell-intrinsic feedback and illustrates how it plays out in early pancreas differentiation. ...
... It should be noted that Delta-endocytosis-independent Notch activation has been reported in tissue culture cells where a Delta ligand has been immobilized to the stiff support of the culture dish [45]. It is also noteworthy that Neur has evolved another type of activity, independently of Delta-Notch, which is to promote epithelial loosening via degradation of the Crumbs-Stardust complex [46,47]. Perhaps events of epithelial to mesenchymal transition triggered by Neur have co-opted Delta expression to accompany this tissue remodeling with the emission of a Delta-Notch signal (e.g., Contreras et al. [48]). ...
... In our first example, we explore the optimal performance of lateral inhibition signaling (LIS). Biologically, LIS is realized by the Delta-Notch pathway (31), which plays a key role in a broad range of self-organized developmental systems (9,(32)(33)(34)(35). In a minimal model of this pathway, each cell i produces a chemical g i , which inhibits the production of the same chemical in neighboring cells (36). ...
... Notch signaling is a pivotal regulator of cell cycle progression and apoptosis that is triggered by binding of Jag or DLL ligands with NOTCH receptors [153,154]. Binding of ligand to its receptor leads to proteolytic cleavages of Notch receptor via metalloproteinase and gamma-secretase, which release and translocate intracellular domain of Notch (Notch-ICD) to the nucleus [155,156]. ICD interacts with CBF1/Su(H)/Lag-1 (CSL) and induces the transcription of several NOTCH target genes such as SLUG, SNAIL1, ZEB1, HEY, HES, and CCND1, while down regulation of CDH1 to promote EMT [155,157,158]. ...
... The pupal notum has been widely used as a model epithelium because it is amenable to live imaging: the animals are immobile, and after dissection from the pupal case, the notum epithelium is easily visualized through the transparent nascent adult cuticle (O'Connor et al., 2022). Our lab has used the notum as a model for epithelial wound healing ~13-15 h APF (Shannon et al., 2017;O'Connor et al., 2021;Stevens et al., 2023), and it has also been used as a model epithelium to analyze cell extrusion and apoptosis (Marinari et al., 2012;Moreno et al., 2018;Valon et al., 2021), mitosis (Besson et al., 2015;Pinheiro et al., 2017), and other epithelial cell behaviors (Guirao et al., 2015). Despite its popularity as a tissue for basic research in epithelial biology, it is unknown when the basement membrane assembles in this tissue. ...
... The most enriched motif matches an ACCGTTA sequence, called F7-BS. The F7-BS motif was defined by a machine learning approach combining statistical analysis to phylogenetic information 33 as the best predictor of functional Svb binding sites in vivo. 28 Although peak calling detected a markedly smaller number of regions for Svb-REP (1,325 with MACS q value = 10e À4 ), regions bound by Svb-REP extensively overlapped with regions bound by Svb-ACT ( Figures 1C and 1D). ...