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The vertebrate planar cell polarity (PCP) pathway has been previously found to control polarized cell behaviors rather than cell fate. We report here that disruption of Xenopus laevis orthologs of the Drosophila melanogaster PCP genes Xint or Xfy affected not only PCP-dependent convergent extension but also caused embryonic phenotypes consistent with defective Hedgehog signaling. These defects in Hedgehog signaling resulted from a broad requirement for Inturned and Fuzzy in ciliogenesis. We show that these proteins are necessary for the formation of both primary cilium in the neural tube and multi-cilia in the epidermis. Also, using Xenopus muco-ciliary epidermis, we demonstrated that one of the core PCP genes Dishevelled performs dual functions in ciliogenesis, basal body docking and planar polarization of ciliary beating. To this end, we showed that Dishevelled works in concert with the PCP effector protein Inturned and Rho GTPase to mediate the docking of basal bodies to the apical cell surface. We suggest that this docking involves a Dvl-dependent association of basal bodies with vesicles, and with the vesicle-trafficking protein Sec8. Finally, we showed that independent of their roles in apical docking, Dvl/PCP signaling is required again for directional ciliary beating. For the first time, this study uncovered the mechanism for controlling the apical docking of basal bodies. Moreover, the results suggest that the same Dvl/PCP signaling is also important for the planar polarization of ciliary beating in a vertebrate muco-ciliary epithelium. / text

During development of the nervous system, signals from specialized organizing centers generate distinct cell types. The signaling molecule, Sonic Hedgehog (SHH) is expressed by the floor plate (FP) and is sufficient to specify the ventral midbrain pattern. In the spinal cord, Bone Morphogenetic Proteins (BMPs) expressed in the roof plate (RP) specify dorsal cell-fates. The attenuation of BMP signaling is required for SHHmediated patterning of the ventral hindbrain and spinal cord, while BMP signaling is required in conjunction with SHH for ventral forebrain patterning. This thesis will focus on the function of SHH and BMPs in the midbrain by examining the molecules ability to pattern and regulate development. Midbrains of Shh[superscript -/-] mice were examined. Some ventral cell fates are specified in the Shh[superscript -/-] mouse in a Ptc1 and Gli1 independent manner. Ventral midbrain induction was observed to be Hh-independent by the existence of a Pax7-negative ventral midbrain territory before embryonic day 9. Interestingly, dorsal markers are not uniformly altered and increased cell death was seen in Shh[superscript -/-] dorsal midbrains. These results suggest specific regulation of dorsal patterning by Shh, rather than a simple deregulation. Several BMPs and their antagonists are expressed in a spatial and temporal manner in the midbrain. Expression of BMPs is seen in the RP, and rostral FP (rFP), which also expresses SHH. BMP signaling was manipulated using in vivo electroporation. NOGGIN misexpression resulted in a loss of RP and a reduction of dorsal cell-fates that was preceded by cell-shape changes, delamination of cells into the lumen and their elimination. This was accompanied by a reduction and alteration of midbrain size and shape. BMP blockade changed N-Cadherin distribution and perturbed pseudostratified morphology of the neurepithelium. Ventrally, BMP blockade resulted in a decrease of proliferation, while increasing differentiation, Notch signaling molecules at the rFP and medial FP markers. However ventral midbrain cell-fates were correctly specified. Notch-Delta signaling was examined in the Mib[superscript -/-] mouse. Different regulation of cell-fates was observed in the midbrain and spinal cord. Mib[superscript -/-] midbrains lacked a mature lateral FP, however ventral cell-fates are specified. Mib[superscript -/-] spinal cords lose Shh expression and several ventral cell-fates. / text

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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Σκοπός: Επειδή η μεγαλύτερη συχνότητα της αναπτυξιακής δυσπλασίας του ισχίου στα θήλεα νεογνά μπορεί να οφείλεται σε ενδοκρινικούς παράγοντες και επίσης έχει βρεθεί ότι το κάπνισμα στη διάρκεια της εγκυμοσύνης προκαλεί ενδοκρινικές διαταραχές, αποφασίσαμε να μελετήσουμε την ανατομία του ισχίου σε νεογνά των οποίων οι μητέρες κάπνιζαν ή δεν κάπνιζαν στην διάρκεια της εγκυμοσύνης. Μεθοδολογία-σχεδιασμός μελέτης: Εξετάσθηκαν κλινικά και υπερηχογραφικά 2066 ισχία, εκ των οποίων 521 αρένων και 512 θηλέων νεογνών. Εξ’ αυτών 48 ήταν άρρενα και 53 θήλεα νεογνά, των οποίων οι μητέρες κάπνιζαν κατά την διάρκεια της εγκυμοσύνης. 93 Αποτελέσματα : Η μέση τιμή ±ΣΑ της γωνίας α στα άρρενα νεογνά των μητέρων οι οποίες δεν κάπνιζαν ήταν 62,3ο ± 5,1ο και των μητέρων οι οποίες κάπνιζαν κατά την εγκυμοσύνη ήταν 62,1ο ± 4,9ο (η διαφορά δεν είναι στατιστικά σημαντική). Στα θήλεα νεογνά των μη καπνιστριών και καπνιστριών μητέρων η α γωνία ήταν 60,7ο ± 5,3ο και 61,9ο ± 4,9ο αντίστοιχα (η διαφορά είναι σημαντική, p= 0,02). Η διαφορά μεταξύ αρρένων και θηλέων νεογνών, τα οποία γεννήθηκαν από μη καπνίστριες μητέρες είναι σημαντική (p<0,000001), ενώ δεν υπήρχε στατιστικώς σημαντική διαφορά μεταξύ αρρένων και θηλέων νεογνών που γεννήθηκαν από καπνίστριες μητέρες. Μεταξύ των θηλέων νεογνών, των οποίων οι μητέρες δεν ήταν καπνίστριες, ο αριθμός των νεογνών με ισχίο τύπου ΙΙα ή χειρότερου ήταν σημαντικά μεγαλύτερος από ότι μεταξύ εκείνων των θηλέων νεογνών, των οποίων οι μητέρες κάπνιζαν. Τα ευρήματα της κλινικής εξέτασης ήταν προς την ίδια κατεύθυνση με εκείνη των υπερηχογραφικών ευρημάτων, γεγονός το οποίο δείχνει ότι το μητρικό κάπνισμα κατά την εγκυμοσύνη προστατεύει το ισχίο στα θήλεα νεογνά. Συμπεράσματα: Το κάπνισμα της μητέρας κατά την διάρκεια της εγκυμοσύνης μειώνει την συχνότητα της υπερηχογραφικής και πιθανότατα της κλινικά διαπιστούμενης αναπτυξιακής δυσπλασίας του ισχίου στα θήλεα, αλλά όχι στα άρρενα νεογνά. Η προστασία του ισχίου η οποία προκαλείται από τον καπνό του τσιγάρου, μπορεί να έχει ενδοκρινική βάση. / Objective: Because the greater frequency of developmental dyplasia of the hip (DDH) in the female could have an endrocrine etiology and maternal smoking in pregnancy causes fetal endocrine disequilibrium, we investigated the anatomy of the hip in neonates of smoking (SM) and nonsmoking mothers (NSM). Study design: Clinical – sonographic examination was performed on 2066 hips of 521 male and 512 female neonates. In 48 male and 53 female neonates the mothers smoked during pregnancy. Results : The mean + SD a angle in the male neonates of the NSM was 62.3ο ± 5.1ο and of the SM 62.1ο ±4.9ο (NS). In the female neonates 95 of the NSM and the SM it was 60.7ο ±5.3ο and 61.9ο ±4.8ο, respectively (p=0.02). The difference between the male and the female neonates of the NSM is significant (p<0.000001), but there is no significant difference between the female neonates of the SM and the male neonates. Among the female neonates whose mothers were nonsmokers the number of those with hip Type IIa or worse was significantly greater that among those whose mothers were smokers. The clinical findings were in the same direction as those of the sonographic findings suggesting hip protection by maternal smoking in the female. Conclusions: Maternal smoking during pregnancy reduces the frequency of sonographic and possibly clinically detected DDH in female but not in male neonates. The tobacco – induced hip protection may have an endocrine basis.

Embryogenesis in plants, as in animals, requires the regulated expression of sets of genes involved in developmental processes. To gain insight into the processes regulating gene expression during embryogenesis differential screening was used to identify embryo-specific sequences in a cDNA library constructed from Zea mays embryo RNA. Four embryo-specific sequences and one constitutive sequence were characterized further by RNA blot hybridization and DNA sequence determination. The constitutive sequence and two of the embryo-specific sequences were found to encode parts of the previously-reported chloroplast 23S rRNA, Oleosin KD-18, and RAB-17 genes. Two sequences, named Emb5 and Emb564, were found to encode novel maize homologs of a gene expressed during late embryogenesis in a wide range of seed plants. These 5 genes exhibited differential temporal and spatial accumulation during development. Moreover, analysis of RNA from cultured embryos suggested that 4 of these genes were regulated by abscisic acid. The ABA-responsive genes could be divided into 3 classes, based on their developmental expression, tissue-specificity, and sensitivity to ABA. Antibodies raised against a $ beta$-galactosidase:EMB564 fusion protein were used to analyze the accumulation of the EMB564 and/or EMB5 proteins. These polyclonal antibodies detected one or several polypeptides with a molecular weight less than 14 kD which exhibited patterns of developmental accumulation and regulation similar to Emb5 and Emb564 transcripts.

Eggs of many organisms contain a store of mRNA which supports protein synthesis during early embryonic development and various regions of the egg cytoplasm are not identical with respect to developmental potential. I investigated the extent to which sea urchin embryogenesis results from a progression of developmental events directed by the embryo, or an expression of a pre-formed maternal program. By the use of two-dimensional electrophoresis I demonstrated that cellular determination during embryonic development at the 16-cell stage is not accompanied by qualitative changes in the distribution within the embryo of abundantly-synthesized proteins, virtually all of which are coded by sequences present in the egg. Using two-dimensional gel electrophoresis, nucleic acid hybridization and molecular cloning, I demonstrated that there is restricted expression of paternal gene mRNA sequences in interspecies hybrid embryos. In some cases, this is due to a posttranscriptional perturbation of gene expression in the hybrid embryos.