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Biomedical subjects

Ulrich Müller

Publications and source records attributed to Ulrich Müller.

At least 19 recordsLinked to original sources

Cadherin 23 is a component of the tip link in hair-cell stereocilia.

Mechanoelectrical transduction, the conversion of mechanical force into electrochemical signals, underlies a range of sensory phenomena, including touch, hearing and balance. Hair cells of the vertebrate inner ear are specialized mechanosensors that transduce mechanical forces arising from sound waves and head movement to provide our senses of hearing and balance; however, the mechanotransduction channel of hair cells and the molecules that regulate channel activity have remained elusive. One molecule that might participate in mechanoelectrical transduction is cadherin 23 (CDH23), as mutations in its gene cause deafness and age-related hearing loss. Furthermore, CDH23 is large enough to be the tip link, the extracellular filament proposed to gate the mechanotransduction channel. Here we show that antibodies against CDH23 label the tip link, and that CDH23 has biochemical properties similar to those of the tip link. Moreover, CDH23 forms a complex with myosin-1c, the only known component of the mechanotransduction apparatus, suggesting that CDH23 and myosin-1c cooperate to regulate the activity of mechanically gated ion channels in hair cells.

Alternative Splicing↗

Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells.

Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (cdh23). Mutations in Cdh23 also cause deafness and vestibular defects in mice and humans, and the protein is present in hair bundles. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputnik(tc317e) larvae. Moreover, tip links are absent in larvae carrying weak alleles of cdh23 that affect mechanotransduction but not hair bundle integrity. We conclude that Cdh23 is an essential tip link component required for hair-cell mechanotransduction.

Alleles↗

Beta1-integrins are critical for cerebellar granule cell precursor proliferation.

We have previously shown that mice with a CNS restricted knock-out of the integrin beta1 subunit gene (Itgb1-CNSko mice) have defects in the formation of lamina and folia in the cerebral and cerebellar cortices that are caused by disruption of the cortical marginal zones. Cortical structures in postnatal and adult Itgb1-CNSko animals are also reduced in size, but the mechanism that causes the size defect has remained unclear. We now demonstrate that proliferation of granule cell precursors (GCPs) is severely affected in the developing cerebellum of Itgb1-CNSko mice. In the absence of beta1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence that beta1 integrins act at least in part cell autonomously in GCPs to regulate their proliferation. Previous studies have shown that sonic hedgehog (Shh)-induced GCP proliferation is potentiated by the integrin ligand laminin. We show that Shh directly binds to laminin and that laminin-Shh induced cell proliferation is dependent on beta1 integrin expression in GCPs. Taken together, these data are consistent with a model in which beta1 integrin expression in GCPs is required to recruit a laminin-Shh complex to the surface of GCPs and to subsequently modulate the activity of signaling pathways that regulate proliferation.

Animals↗

Maps of nonadiabatic coupling in triatomic hydrogen.

We show in an experiment that dissociation of state-selected neutral H3* molecules into three ground-state hydrogen atoms reveals highly structured maps of correlation in the motion of the three atoms. These maps provide a direct view of the internal molecular couplings which initiate dissociation.

Journal Article↗

Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.

Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of approximately 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development.

Animals↗

Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism.

X-linked dystonia parkinsonism (XDP) is an X-linked recessive adult onset movement disorder characterized by both dystonia and parkinsonism. We report delineation of the disease gene within a 300-kb interval of Xq13.1 by allelic association. Sequencing of this region in a patient revealed five disease-specific single-nucleotide changes (here referred to as DSC) and a 48-bp deletion unique to XDP. One of the DSCs is located within an exon of a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of three different transcription start sites that encode four different transcripts. Two of these transcripts include distal portions of the TAF1 gene (TATA-box binding protein-associated factor 1) and are alternatively spliced. Three exons overlap with ING2 (a putative tumor suppressor) and with a homologue of CIS4 (cytokine-inducible SH2 protein 4), both of which are encoded by the opposite strand. Although all DSCs are located within this multiple transcript system, only DSC3 lies within an exon. This exon is used by all alternative transcripts making a pathogenic role of DSC3 in XDP likely. The multiple transcript system is therefore referred to as DYT3 (disease locus in XDP).

Adult↗

Neuroimaging of serotonin transporters in post-stroke pathological crying.

Pathological crying (PC) is a neuropsychiatric disorder characterized by an excessive tendency towards crying after brain damage. To elucidate the role of serotonin neurotransmission for PC, a pilot study was performed using single photon emission computed tomography with [123I]beta-CIT to estimate central (midbrain/pons and thalamus/hypothalamus) serotonin transporter (SERT) densities in 15 stroke patients who did or did not have PC. SERT binding ratios in midbrain/pons were significantly lower in the PC subgroup.

Brain↗

Dementia with Lewy bodies: disease concept and genetics.

Dementia with Lewy bodies (DLB) was first recognized as a clinicopathological entity about 20 years ago. It is the second most-common degenerative dementia after Alzheimer's disease. Clinically, DLB differs from Alzheimer's disease in that disease symptoms are prone to fluctuate and patients often suffer from visual hallucinations, while short-term memory is relatively preserved. As many as 70% of patients have parkinsonism and up to 50% are sensitive to the extrapyramidal side effects of neuroleptic drugs. About 3 million Europeans will be affected by DLB in 2020 if no cure or effective treatment is found. This article reviews the current disease concept, as well as existing problems concerning classification and delineation of DLB from other conditions with dementia. The literature on genetic findings in this complex disease is critically discussed.

Humans↗

Lack of association of interleukin-10 promoter region polymorphisms with Alzheimer's disease.

There is increasing evidence that immune mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recently, polymorphisms of the interleukin (IL)-1 and IL-6 genes were found to be associated with late-onset AD. The immunoregulatory IL-10 downregulates synthesis of pro-inflammatory cytokines such as IL-1. Current evidence suggests that some polymorphisms in the IL-10 promoter may have functional effects on IL-10 transcription. A total of 406 German AD patients (mean age 70.2+/-10.0 years, range 50-95 years, 42% female) and 251 unrelated non-demented control subjects (mean age 66.8+/-10.6 years, range 50-93 years, 38% female) were investigated for the presence of three polymorphisms in the IL-10 promoter region (-1087A/G, -824C/T, -597C/A). No significant differences in the allelic distribution of the analyzed IL-10 polymorphisms have been found between AD patients and controls. We conclude that polymorphisms in the IL-10 promoter region do not increase the risk of developing AD.

Aged↗

Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC.

Mutations in SDHC cause autosomal dominant paraganglioma, type 3 (PGL3), and have to date been demonstrated in only one family. Here, we report on a novel mutation in a patient with a malignant, catecholamine-producing paraganglioma at the carotid bifurcation. The mutation is a G-->T transversion at position +1 of intron 5 of the SDHC gene, leading to the deletion of exon 5 and a shift in the reading frame.

Adult↗

Is correction for age necessary in neuroimaging studies of the central serotonin transporter?

The central neurotransmitter serotonin plays a major role in a number of neuropsychiatric disorders. However, results from post-mortem and in vivo neuroimaging studies of the influence of age on the number of presynaptic serotonin transporters (SERT) are controversial. To provide further evidence of relevance for this ongoing discussion, SERT were imaged in 22 persons without neuropsychiatric impairment using [(123)I]2beta-carbomethoxy-3beta-(iodophenyl)tropane ([(123)I]beta-CIT) and high-resolution single-photon emission tomography (SPET). The SPET analysis method was based on magnetic resonance image co-registration in order to quantify SERT with acceptable inter- and intra-observer variability. Using this technique, we found a significant age-related decline in the thalamic/hypothalamic and midbrain/upper brainstem SERT density, which was more pronounced than that previously reported in the literature. From these results we conclude that age-related changes in SERT density need to be considered in future clinical studies.

Adolescent↗

Beta1 integrins regulate myoblast fusion and sarcomere assembly.

The mechanisms that regulate the formation of multinucleated muscle fibers from mononucleated myoblasts are not well understood. We show here that extracellular matrix (ECM) receptors of the beta1 integrin family regulate myoblast fusion. beta1-deficient myoblasts adhere to each other, but plasma membrane breakdown is defective. The integrin-associated tetraspanin CD9 that regulates cell fusion is no longer expressed at the cell surface of beta1-deficient myoblasts, suggesting that beta1 integrins regulate the formation of a protein complex important for fusion. Subsequent to fusion, beta1 integrins are required for the assembly of sarcomeres. Other ECM receptors such as the dystrophin glycoprotein complex are still expressed but cannot compensate for the loss of beta1 integrins, providing evidence that different ECM receptors have nonredundant functions in skeletal muscle fibers.

Animals↗

[Compulsive-obsessive disorder after severe head trauma: diagnosis and treatment].

An 18-year-old man suffered a severe head trauma from a car accident. Eight months later the patient had a good general state of health. But at this time he was referred to our psychiatric hospital and he reported increased checking compulsions and aggressive obsessions. In addition there was increased impulsivity. The patient was treated with an selective-serotonin-reuptake-inhibitor (SSRI) and showed a clinical response. Obsessive-compulsive disorder (OCD) has rarely been described after traumatic brain injury. Clinical symptoms, neuropsychological dysfunctions, brain imaging and therapy are illustrated. The represented connections of the frontal brain lesions and OCD-symptoms with interventions in the serotonin system support the neurobiological hypotheses of the obsessive-compulsive disorder.

Adult↗

Glomerular and renal vascular structural changes in alpha8 integrin-deficient mice.

Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the alpha8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. alpha8-deficient (alpha8-/-) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of alpha8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of alpha8-/- mice would be completely normal. Therefore, the renal phenotype of adult alpha8-/- mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. alpha8-/- mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and alpha8-/- mice. Quantitative morphologic analyses revealed that the glomeruli of alpha8-/- mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the alpha8 ligand fibronectin) was expanded in alpha8-/- mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of alpha8-/- mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor alpha2 integrin in alpha8-/- mice. The glomerular capillary length density was significantly greater in alpha8-/- mice than in wild-type mice. Cortical arterial vessel walls were not altered in alpha8-/- mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of alpha8, glomerular and renal vascular alterations in alpha8-/- mice were relatively mild. Only aged alpha8-/- mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of alpha8 can be largely compensated for, at least in younger alpha8-/- mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor alpha2 contribute to maintaining the glomerular structure in alpha8-/- mice. The compensatory mechanisms involved will be the subject of future research.

Animals↗

The development of executive function in early childhood.

According to the Cognitive Complexity and Control (CCC) theory, the development of executive function can be understood in terms of age-related increases in the maximum complexity of the rules children can formulate and use when solving problems. This Monograph describes four studies (9 experiments) designed to test hypotheses derived from the CCC theory and from alternative theoretical perspectives on the development of executive function (memory accounts, inhibition accounts, and redescription accounts). Each study employed a version of the Dimensional Change Card Sort (DCCS), in which children are required first to sort cards by one pair of rules (e.g., color rules: "If red then here, if blue then there"), and then sort the same cards by another, incompatible pair of rules (e.g., shape rules). Study 1 found that although most 3- to 4-year-olds failed the standard version of this task (i.e., they perseverated on the preswitch rules during the postswitch phase), they usually performed well when they were required to use four rules (including bidimensional rules) and those rules were not in conflict (i.e., they did not require children to respond in two different ways to the same test card). These findings indicate that children's perseveration cannot be attributed in a straightforward fashion to limitations in children's memory capacity. Study 2 examined the circumstances in which children can use conflicting rules. Three experiments demonstrated effects of rule dimensionality (uni- vs. bidimensional rules) but no effects of stimulus characteristics (1 vs. 2 test cards; spatially integrated vs. separated stimuli). Taken together, these studies suggest that conflict among rules is a key determinant of difficulty, but that conflict interacts with dimensionality. Study 3 examined what types of conflict pose problems for 3- to 4-year-olds by comparing performance on standard, Partial Change, and Total Change versions of the DCCS. Results revealed effects of conflict at the level of specific rules (e.g., "If red, then there"), rather than specific stimulus configurations or dimensions per se, indicating that activation of the preswitch rules persists into the postswitch phase. Study 4 examined whether negative priming also contributes to difficulty on the DCCS. Two experiments suggested that the active selection of preswitch rules against a competing alternative results in the lasting suppression of the alternative. Taken together, the results of these studies provide the basis for a revision of the CCC theory (CCC-r) that specifies more clearly the circumstances in which children will have difficulty using rules at various levels of complexity, provides a more detailed account of how to determine the complexity of rules required in a task, takes account of both the activation and inhibition of rules as a function of experience, and highlights the importance of taking intentionality seriously in the study of executive function.

Attention↗

Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development.

Neuregulins and their Erbb receptors have been implicated in neuromuscular synapse formation by regulating gene expression in subsynaptic nuclei. To analyze the function of Erbb2 in this process, we have inactivated the Erbb2 gene in developing muscle fibers by Cre/Lox-mediated gene ablation. Neuromuscular synapses form in the mutant mice, but the synapses are less efficient and contain reduced levels of acetylcholine receptors. Surprisingly, the mutant mice also show proprioceptive defects caused by abnormal muscle spindle development. Sensory Ia afferent neurons establish initial contact with Erbb2-deficient myotubes. However, functional spindles never develop. Taken together, our data suggest that Erbb2 signaling regulates the formation of both neuromuscular synapses and muscle spindles.

Actins↗

The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions.

Usher syndrome type 1 (USH1) patients suffer from sensorineuronal deafness, vestibular dysfunction, and visual impairment. Several genetic loci have been linked to USH1, and four of the relevant genes have been identified. They encode the unconventional myosin VIIa, the PDZ-domain protein harmonin, and the putative adhesion receptors cadherin 23 (CDH23) and protocadherin 15 (PCDH15). We show here that CDH23 and harmonin form a protein complex. Two PDZ domains in harmonin interact with two complementary binding surfaces in the CDH23 cytoplasmic domain. One of the binding surfaces is disrupted by sequences encoded by an alternatively spliced CDH23 exon that is expressed in the ear, but not the retina. In the ear, CDH23 and harmonin are expressed in the stereocilia of hair cells, and in the retina within the photoreceptor cell layer. Because CDH23-deficient mice have splayed stereocilia, our data suggest that CDH23 and harmonin are part of a transmembrane complex that connects stereocilia into a bundle. Defects in the formation of this complex are predicted to disrupt stereocilia bundles and cause deafness in USH1 patients.

Amino Acid Sequence↗

Reelin, Disabled 1, and beta 1 integrins are required for the formation of the radial glial scaffold in the hippocampus.

The extracellular matrix molecule Reelin is required for the correct positioning of neurons during the development of the forebrain. However, the mechanism of Reelin action on neuronal migration is poorly understood. Reelin is assumed to act on neurons directly, but it may also affect the differentiation of glial cells necessary for neuronal migration. Here we show that a regular glial scaffold fails to form in vivo in the dentate gyrus of mice deficient of Reelin or Disabled 1, a neuronal adaptor protein in the Reelin signaling pathway. A subset of these defects is observed in mice that lack beta(1)-class integrins, known to bind Reelin. Moreover, recombinant Reelin induced branching of glial processes in vitro. Our data suggest that Reelin affects glial differentiation via Disabled 1 and beta(1)-class integrin-dependent signaling pathways.

Animals↗