The prolactin releasing peptides: RF-amide peptides

Although dopamine is considered the major hypothalamic controller of prolactin release from the anterior pituitary gland, there is evidence that a yet to be discovered prolactin releasing factor (PRF) also exists in brain. Recently, two peptides were isolated, products of the same prohormone, that were reported to have significant prolactin-releasing activity. These peptides, called prolactin releasing peptides, are not accepted by all investigators to be in fact PRFs. Instead, it appears that their widespread distribution in brain and the presence of receptors for the peptides in sites unrelated to neuroendocrine function are the basis for a variety of central nervous system action including activation of the autonomic nervous system. Thus, these peptides may not be PRFs, but instead neuroactive agents that are involved in many brain circuits with divergent functions.     

Role for sperm in spatial patterning of the early mouse embryo

Despite an apparent lack of determinants that specify cell fate, spatial patterning of the mouse embryo is evident early in development. The axis of the post-implantation egg cylinder can be traced back to organization of the pre-implantation blastocyst. This in turn reflects the organization of the cleavage-stage embryo and the animal-vegetal axis of the zygote. These findings suggest that the cleavage pattern of normal development may be involved in specifying the future embryonic axis; however, how and when this pattern becomes established is unclear. In many animal eggs, the sperm entry position provides a cue for embryonic patterning, but until now no such role has been found in mammals. Here we show that the sperm entry position predicts the plane of initial cleavage of the mouse egg and can define embryonic and abembryonic halves of the future blastocyst. In addition, the cell inheriting the sperm entry position acquires a division advantage and tends to cleave ahead of its sister. As cell identity reflects the timing of the early cleavages, these events together shape the blastocyst whose organization will become translated into axial patterning after implantation. We present a model for axial development that accommodates these findings with the regulative nature of mouse embryos.     

The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy

Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.     

Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice

The autosomal recessive mouse mutation quivering (qv), which arose spontaneously in 1953, produces progressive ataxia with hind limb paralysis, deafness and tremor. Six additional spontaneous alleles, qvJ, qv2J, qv3J, qv4J, qvlnd and qvlnd2J, have been identified. Ear twitch responses (Preyer's reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory information, indicating that, in contrast to the many known mutations causing deafness originating in the cochlea, deafness in qv is central in origin. Here we report that quivering mice carry loss-of-function mutations in the mouse beta-spectrin 4 gene (Spnb4) that cause alterations in ion channel localization in myelinated nerves; this provides a rationale for the auditory and motor neuropathies of these mice.     

The core of the motor domain determines the direction of myosin movement

Myosins constitute a superfamily of at least 18 known classes of molecular motors that move along actin filaments. Myosins move towards the plus end of F-actin filaments; however, it was shown recently that a certain class of myosin, class VI myosin, moves towards the opposite end of F-actin, that is, in the minus direction. As there is a large, unique insertion in the myosin VI head domain between the motor domain and the light-chain-binding domain (the lever arm), it was thought that this insertion alters the angle of the lever-arm switch movement, thereby changing the direction of motility. Here we determine the direction of motility of chimaeric myosins that comprise the motor domain and the lever-arm domain (containing an insert) from myosins that have movement in the opposite direction. The results show that the motor core domain, but neither the large insert nor the converter domain, determines the direction of myosin motility.