The Drosophila melanogaster flightless I gene is required for normal cellularization of the syncytial blastoderm. Highly conserved homologues of flightless I are present in Caenorhabditis elegans, mouse, and human. We have disrupted the mouse homologue Fliih by homologous recombination in embryonic stem cells. Heterozygous Fliih mutant mice develop normally, although the level of Fliih protein is reduced. Cultured homozygous Fliih mutant blastocysts hatch, attach, and form an outgrowing trophoblast cell layer, but egg cylinder formation fails and the embryos degenerate. Similarly, Fliih mutant embryos initiate implantation in vivo but then rapidly degenerate. We have constructed a transgenic mouse carrying the complete human FLII gene and shown that the FLII transgene is capable of rescuing the embryonic lethality of the homozygous targeted Fliih mutation. These results confirm the specific inactivation of the Fliih gene and establish that the human FLII gene and its gene product are functional in the mouse. The Fliih mouse mutant phenotype is much more severe than in the case of the related gelsolin family members gelsolin, villin, and CapG, where the homozygous mutant mice are viable and fertile but display alterations in cytoskeletal actin regulation.We are studying the mammalian homologues of a number of Drosophila melanogaster genes concerned with development or behavior, as part of a program aimed at identifying novel mammalian developmental and neurobiological genes. The D. melanogaster flightless I (fliI) gene (4,15,23,24,33) is required for cellularization of the syncytial blastoderm. With severe mutations in fliI, when the contribution of maternal product is eliminated, cellularization is only partial and gastrulation fails (35,44).

Mutations in myosin XVA are responsible for the shaker 2 (sh2) phenotype in mice and nonsyndromic autosomal recessive profound hearing loss DFNB3 on chromosome 17p11.2. We have ascertained seven families with profound congenital hearing loss from Pakistan and India with evidence of linkage to DFNB3 at 17p11.2. We report three novel homozygous mutations in MYO15A segregating in three of these families. In addition, one hemizygous missense mutation of MYO15A was found in one of eight Smith-Magenis syndrome (del(17)p11.2) patients from North America who had moderately severe sensorineural hearing loss.

N-methyl-D-aspartate (NMDA) receptors (NMDARs) are implicated in synaptic plasticity and modulation of glutamatergic excitatory transmission. Effect of NMDAR activation on inhibitory GABAergic transmission remains largely unknown. Here, we report that a brief application of NMDA could induce two distinct actions in CA1 pyramidal neurons in mouse hippocampal slices: 1) an inward current attributed to activation of postsynaptic NMDARs; and 2) fast phasic synaptic currents, namely spontaneous inhibitory postsynaptic currents (sIPSCs), mediated by GABA(A) receptors in pyramidal neurons. The mean amplitude of sIPSCs was also increased by NMDA. This profound increase in the sIPSC frequency and amplitude was markedly suppressed by the sodium channel blocker TTX, whereas the frequency and mean amplitude of miniature IPSCs were not significantly affected by NMDA, suggesting that NMDA elicits repetitive firing in GABAergic interneurons, thereby leading to GABA release from multiple synaptic sites of single GABAergic axons. We found that the NMDAR open-channel blocker MK-801 injected into recorded pyramidal neurons suppressed the NMDA-induced increase of sIPSCs, which raises the possibility that the firing of interneurons may not be the sole factor and certain retrograde messengers may also be involved in the NMDA-mediated enhancement of GABAergic transmission. Our results from pharmacological tests suggest that the nitric oxide signaling pathway is mobilized by NMDAR activation in CA1 pyramidal neurons, which in turn retrogradely facilitates GABA release from the presynaptic terminals. Thus NMDARs at glutamatergic synapses on both CA1 pyramidal neurons and interneurons appear to exert feedback and feedforward inhibition for determining the spike timing of the hippocampal microcircuit.

The Smith‐Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation syndrome associated with a deletion of chromosome 17p11.2. Since the recognition of this disorder as a clinical entity in 1982, the phenotypic features of SMS have been well described. Unfortunately, the often subtle physical and chromosomal findings of SMS may preclude the diagnosis in some affected individuals. This article offers a comprehensive review of more than 100 SMS patients whose cases have been reported, including details of the more recently studied clinical aspects of SMS. SMS has been postulated to be a contiguous gene deletion syndrome. Currently, only a few genes have been mapped to the SMS critical region. Further research (including genotype‐phenotype correlation) is needed to identify the gene or genes that, when deleted, cause this disorder. Although the molecular etiology of SMS is unknown, recent investigations have identified multiple repetitive sequences within the SMS region. As described in other human disorders, repetitive sequences may be involved in homologous recombination and cause deletion. The advances in the molecular dissection of the SMS region are described, and hypotheses regarding the molecular mechanisms of SMS are offered. Parallels are made between the SMS region and other regions in the human genome where the molecular etiologies of diseases have been elucidated. © 1996 Wiley‐Liss, Inc.