Seminars in Developmental Biology最新文献

Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development the features of which include conductive hearing loss and cleft palate; diagnosis is complicated by marked variability in expression. Whilst the underlying genetic defect is unknown it is thought to be due to an abnormality of neural crest cell migration. The mutated gene has been mapped to chromosome 5q32-33.1, a high resolution genetic and radiation hybrid map surrounding the locus created, and flanking markers identified. The critical region has subsequently been cloned in yeast artificial chromosome and attempts to isolate the mutated gene are in progress.

The association between different congenital anomalies, in the form of recognisable single gene syndromes, provides possible clues to developmental genes or processes that are common to more than one body region. Many syndromes, although apparently genetically distinct, do show phenotypic similarities. Such communities of syndromes might reflect common developmental pathways. This paper reviews some human syndromes associated with both craniofacial and limb defects, concentrating on conditions that have either been mapped or where specific mutations have been identified, or which form part of an apparent syndrome community.

Sea urchin sperm species-specifically adhere to the egg surface during fertilization. The protein which mediates this adhesion is known as bindin and cDNAs have recently been cloned and sequenced from several different species. Bindin proteins contain a highly conserved central domain flanked by much more highly divergent amino- and carboxyl-terminal domains. Investigations of the structure and function relationships indicate that the conserved domains may participate in membrane fusion and sulfated fucan binding activities, which may be conserved functions of bindin. The species-specific adhesion activity appears to be duplicated in both the amino- and carboxyl-terminal domain and may correspond to repeated sequence motifs found in these domains. The duplication of these sequence motifs and the redundancy of the adhesive domains may be important for the molecular mechanism of bindin evolution during speciation.

Using monoclonal antibodies that inhibit function, two cell surface proteins involved in gamete interactions were identified on guinea-pig sperm. Homologs of both the proteins have been identified in a number of mammalian species. One of the proteins, PH-20, has a function in sperm-zona binding and also has hyaluronidase activity. The other, named fertilin, is a heterodimer involved in sperm-egg membrane adhesion and also has a possible role in membrane fusion itself. Additionally, the precursor form of fertilin has potential metalloprotease activity. The functions of these proteins in gamete interactions range from the first physical contact between the sperm and cumulus cells to the final membrane interactions of sperm and egg leading to fusion.

Spermatozoa should bind to and then penetrate the vitelline coat for fertilization in ascidians and many other animals. There is substantial evidence that the binding of ascidian sperm is mediated by a sperm glycosidase and complementary saccharide chains of glycoproteins in the vitelline coat. Involvement of a sperm proteasome in the binding is also suggested. For the penetration, sperm proteases such as chymotrypsin-like enzyme, acrosin, spermosin and proteasome are suggested to play essential roles. Sperm glycosidase, that is translocated from the tip of sperm head to the surface overlying the mitochondrion, anchors the mitochondrion at the outer surface of vitelline coat. Therefore it assists sperm to penetrate the vitelline coat and traverse the perivitelline space. For fusion with egg plasma membrane, sperm metalloendoprotease seems to be involved. Egg glycosidases and proteases serve for some steps after fertilization, such as the prevention of polyspermy, expansion of perivitelline space and regulation of cell cycle.

Recent studies of mouse fertilization have identified two complementary gamete receptors that mediate sperm-egg binding. Sperm surface β1,4-galactosyltransferase (GalTase) binds to specific oligosaccharides of the egg coat (zona pellucida) glycoprotein ZP3. Evidence suggests that these same molecules may stimulate the acrosome reaction in sperm. After the acrosome reaction, it is thought that sperm remain adherent to the zona by binding another glycoprotein, ZP2. The acrosome-reacted sperm releases hydrolytic enzymes, including acrosin and N-acetylglucosaminidase, enabling it to penetrate the zona pellucida. After the penetrating sperm binds to the egg membrane and activates development, N-acetylglucosaminidase is exocytosed from egg cortical granules and, as part of the zona block to polyspermy, globally removes the sperm GalTase binding site from ZP3 oligosaccharides.

The non-motile sperm of Sicyonia ingentis, mixed with eggs by a spawning female, undergo a primary binding to the vitelline envelope (VE) of the oocyte. Once bound to the VE, sperm undergo exocytosis of the acrosomal vesicle, penetrate the VE, and secondarily bind to a surface coat that is closely associated with the oolemma. Unreacted sperm preincubated with solubilized VE components exhibit diminished binding to VEs in a concentration dependent manner. The ligand responsible for this binding is a carbohydrate moiety in the VE. The ligand preferentially binds to the anterior tip of unreacted sperm, as demonstrated with anti-VE polyclonal antibodies. Acrosome intact sperm will not bind to surface coats; however, acrosome reacted sperm do bind to surface coats via an externalized acrosomal granule.

Peptides released from sea urchin eggs bind to and activate receptors in the sperm plasma membrane. The activated receptors cause multiple physiological changes in the sperm cell, including increased synthesis of cyclic GMP, that result in kinetic and directional changes in motility. Egg peptides appear to activate spermatozoa only from sea urchins in the same taxonomic order. The amino acid sequences of two different apparent receptors for the peptides reveal that one is a receptor/guanylyl cyclase. The mechanism by which the other putative receptor signals, if in fact it signals, is not known. Mammalian receptors homologous to both types of sperm-activating peptide receptors have been found in somatic cells. Thus, proteins that carry out communication between gametes of ancient invertebrates may be considered prototypes for the evolution of signaling molecules in animals that are morphologically more complex.

Abalone sperm lysin is a 16 kDa protein that creates a hole in the egg vitelline envelope (VE) to allow the sperm to fuse with the egg. Purified lysin exhibits quantitative species-specificity in the dissolution of isolated VE. The molecular basis for this specificity has been studied by sequencing lysin cDNA and by solving the lysin crystal structure. In the deduced amino acid sequences of lysins of seven species of California abalones 50% of the positions are invariant. The most highly variable and strictly species-specific region is the amino-terminal domain of residues 2-12. The crystal structure of lysin reveals a highly α-helical protein with a novel fold. Two tracks of basic amino acids run the length of the molecule. A hydrophobic patch of 11 residues lies on the opposite surface from the basic tracks. The species-specific domain of positions 2-12 extends away from the helical core. Mapping the species-variable positions onto the lysin structure indicates regions which could be involved in species-specific molecular recognition.