The sexual dimorphic position of the gonads in mammals is dependent on differential development of two ligaments, the cranial suspensory ligament (CSL) and the gubernaculum. During male embryogenesis, outgrowth of the gubernaculum and regression of the CSL result in transabdominal descent of the testes, whereas in the female, development of the CSL in conjunction with failure of the gubernaculum development holds the ovaries in a position lateral to the kidneys. Several lines of evidence suggest that regression of the CSL and induction of gubernaculum development are mediated by testosterone and a yet unidentified testicular factor, respectively. The Insl3 gene (originally designated Ley I-L), a member of the insulin-like superfamily, is specifically expressed in Leydig cells of the fetal and postnatal testis and in theca cells of the postnatal ovary. Here we show that male mice homozygous for a targeted deletion of the Insl3 locus exhibit bilateral cryptorchidism with free moving testes and genital ducts. These malformations are due to failure of gubernaculum development during embryogenesis. In double-mutant male mice for Insl3 and androgen receptor genes, testes are positioned adjacent to the kidneys and steadied in the abdomen by the CSL. These findings demonstrate, that the Insl3 induces gubernaculum development in an androgen-independent way, while androgen-mediated regression of the CSL occurs independently from Insl3.

The Sox genes define a family of transcription factors that play a key role in the determination of cell fate during development. The preferential expression of the Sox15 in the myogenic precursor cells led us to suggest that the Sox15 is involved in the specification of myogenic cell lineages or in the regulation of the fusion of myoblasts to form myotubes during the development and regeneration of skeletal muscle. To identify the physiological function of Sox15 in mice, we disrupted the Sox15 by homologous recombination in mice. Sox15-deficient mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. Histological analysis revealed the normal ultrastructure of myofibers and the presence of comparable amounts of satellite cells in the skeletal muscles of Sox15

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Mutations in either the Drosophila melanogaster pelota or pelo gene or the Saccharomyces cerevisiae homologous gene, DOM34, cause defects of spermatogenesis and oogenesis in Drosophila, and delay of growth and failure of sporulation in yeast. These phenotypes suggest that pelota is required for normal progression of the mitotic and meiotic cell cycle. To determine the role of the pelota in mouse development and progression of cell cycle, we have established a targeted disruption of the mouse Pelo. Heterozygous animals are variable and fertile. Genotyping of the progeny of heterozygous intercrosses shows the absence of Pelo ؊/؊ pups and suggests an embryo-lethal phenotype. Histological analyses reveal that the homozygous Pelo deficient embryos fail to develop past day 7.5 of embryogenesis (E7.5). The failure of mitotic active inner cell mass of the Pelo ؊/؊ blastocysts to expand in growth after 4 days in culture and the survival of mitotic inactive trophoplast indicate that the lethality of Pelo-null embryos is due to defects in cell proliferation. Analysis of the cellular DNA content reveals the significant increase of aneuploid cells in Pelo ؊/؊ embryos at E7.5. Therefore, the percent increase of aneuploid cells at E7.5 may be directly responsible for the arrested development and suggests that Pelo is required for the maintenance of genomic stability.The Pelo gene was originally identified in a mutagenesis screen for spermatogenesis-specific genes of Drosophila melanogaster (7). Spermatogenesis in pelo mutants progresses normally during the four mitotic divisions, and the 16 spermatocytes undergo a premeiotic S-phase and duplicate their DNA content. However, spermatocytes in the mutant arrested prior to full chromosome condensation, spindle pole organization, and nuclear breakdown. Metaphase and anaphase figures of the meiotic divisions, which are clearly recognized in squashed preparations of wild-type testis, were not observed in testis of the pelo mutant. Although meiotic division arrests in pelo spermatocytes, germ cell differentiation continues, resulting in 4N spermatids with head and tail structures. These results indicate that the Pelo is required for the meiotic division during the G 2 /M transition (10). Beside the effect of the mutation on spermatogenesis, the eyes of the pelo homozygotes are up to 30% smaller than those of wild-type siblings, and the ovaries in mutants are very small. In contrast to the arrest in meiotic divisions in male germ cells, during oogenesis the mitotic divisions are affected. The mitotic zone of ovaries appears disorganized and often contains degenerating cells. Despite the apparent phenotype observed in the gametogenesis of Drosophila mutant, the pelo transcripts are not restricted to germ cells but also detected in early embryonic development.Analysis of mitotic and meiotic division in the dom34 mutant of Saccharomyces cerevisiae, which has a mutation in the pelota orthologous gene, reveals that the dom34 mutant exhibits a growth delay and fails to undergo sporulation pr...

In 32 human embryos from 5 to 27 mm of length, stages 13 to 23 (according to the Carnegie system of stages), the contributions of the sinus venosus septum and the right sinus valve of the right atrium to the formation of the Eustachian and Thebesian valve were examined by scanning electron microscopy. The sinus septum takes part in the subdivision of the right sinus valve into the Eustachian and the Thebesian valves. From its first origin the sinus septum forms a septal structure between the orifices of the right hepatic vein (hepatic portion of the inferior caval vein), the precursor of the inferior caval vein, and the left horn of the sinus venosus, the precursor of the coronary sinus. Before the incorporation of the sinus venosus into the right atrium, it has an intra-sinusal position, and extends between the bases of the left and the right sinus valve. During the incorporation of the sinus venosus into the right atrium the sinus septum receives an intra-atrial position, and its positional relationships to the sinus valves and the orifices of the corresponding veins remain unchanged in principle. Due to the connection between the sinus septum and the right sinus valve, after completion of the incorporation of the sinus, the superior portion of the right sinus valve branches y-like into a lateral limb, (i.e. its original inferior portion) and into a medial limb, (i.e. the sinus septum).(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the present study is to examine whether the formation of the cranial and cervical flexures is involved in the process of cardiac looping, and whether looping anomalies are causally involved in the development of cardiac malformations. For this purpose, the formation of the cranial and cervical flexures was experimentally suppressed in chick embryos by introducing a straight human hair into the neural tube. In the experimental embryos, the absence of the cervical flexure, alone or in combination with a reduced cranial flexure, was always associated with anomalies in the looping of the tubular heart. The convergence of the primary distant venous and arterial ends of the heart, as well as the normal movement of the ventricular region from its original position, cranial and ventral from the cardiac inflow, to its final position caudal to the presumptive atria, was suppressed to an extent related to the degree to which the formation of the flexures was prevented. Positional immaturity of the heart loop (increased distance between its inflow and outflow, and cranio-ventral position of the ventricular region) was associated with incomplete deformations (reduced angulations) of the cardiac wall at the atrioventricular or conoventricular junctional areas. Reduced angulations were associated with the hypoplasia of the anlagen of the cardiac septa at the level of the angulation (av-cushions, conal ridges). Hypoplasia of these anlagen was followed by incomplete or absent fusion of their opposite free edges, which finally resulted in atrioventricular or ventricular septal defects. These results show that the convergence of the venous and arterial ends of the tubular heart and the caudo-dorsal movement of its ventricular region are related to the formation of the cervical flexure, and that the mesenchymal septa of the heart seem to develop in response to deformations of the embryonic heart, which are generated by the process of cardiac looping. Therefore, the positional and morphological changes of the looping heart are regarded as playing a key role in the process of normal and abnormal morphogenesis of the heart.

The formation of the relief of cardiac septa occurs in connexion with the development of shape of the external cardiac wall. Changes in the form of the external cardiac wall precede changes in the internal cardiac wall. The originally straight tubular heart is angulated at typical sites during cardiac looping. At the site of angulations the primary circular cross-section is deformed to an oval and is thereby narrowed. This deformation causes a growth of the endocardial and subendocardial tissue along the long sides of the oval to form protrusions into the cardiac lumen. These protrusions represent the anlagen of the fibrous cardiac septa. The site of origin of the fibrous septa is directly dependent on the direction of primary deformation. Origin and site of the ventricular septum results from the locally different directions and patterns of growth in the right and left ventricle. The anlagen of the cardiac septa are not isolated formations, but rather represent a continuous system of protrusions. Depending on the position and form of its components, their free edges grow towards each other and fuse wherever they meet.

Testicular descent in mice is dependent upon proper outgrowth of the gubernaculum primordia under the influence of the insulin-like 3 gene product (Insl3). Deletion of this gene prevents gubernaculum growth and causes bilateral cryptorchidism. In vitro experiments have led to the suggestion that Insl3 and androgens together induce outgrowth of the gubernacular primordia. The experiments reported here were designed specifically to determine whether in vivo the Insl3-mediated gubernaculum development is independent of androgens. To that effect transgenic male and female mice were generated that overexpressed Insl3 in the pancreas during fetal and postnatal life. Expression of the transgenic allele in the Insl3-deficient mice rescued the cryptorchidism in male mutant, indicating that the islet beta-cells efficiently processed the Insl3 gene product to the functional hormone. All transgenic females displayed bilateral inguinal hernia. The processus vaginalis developed containing intestinal loops. The Müllerian derivatives gave rise to oviduct, uterus, and upper vagina, and Wolffian duct derivatives were missing, indicating the absence of the androgen- and anti-Müllerian hormone-mediated activities in transgenic females. The ovaries descended into a position over the bladder and attached to the abdominal wall via the well developed cranial suspensory ligament and the gubernaculum. Administration of dihydrotestosterone during prenatal development suppressed formation of the cranial suspensory ligament and thereby allowed the descent of the ovaries into the processus vaginalis. These results suggest that Insl3-mediated activity induces gubernaculum development and precludes a role of androgen in this process. Furthermore, the transgenic females exhibit reduced fertility, which is due to fetal mortality during midgestation.