Biomedical subjects

Andreas H Kottmann

Publications and source records attributed to Andreas H Kottmann.

4 recordsLinked to original sources

PubMed2006

Fmrp is required for the establishment of the startle response during the critical period of auditory development.

Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the FMR-1 gene product FMRP. In addition to the hallmark cognitive defect, other symptoms are also apparent including hyperactivity, seizures and sensory abnormalities including a characteristic increase in sensitivity to auditory, tactile, visual, and olfactory stimuli. Fragile X is a developmental disorder with the first symptoms apparent in the first year of life but little is known about the role of FMRP in developmental processes. The sensory hyperreactivity of fragile X can be reproduced in fmr-1 knockout (KO) mice evident as abnormal audiogenic startle response and increased audiogenic seizure susceptibility. Here, we studied the onset and emergence of the startle deficit in fmr-1 KO mice during development. The startle response was first detectable at the end of the 2nd postnatal week in wild-type mice. The amplitude of startle response showed a substantial increase until the 4th postnatal week followed by a further but moderate increase up to adulthood. Expression of the fmr1 gene was detectable in the startle circuit before the onset and throughout the development of the startle response. Although the onset and amplitude of the startle response were not altered in fmr1 KO mice until the 3rd-4th postnatal week, beyond this age it failed to develop further resulting in an overall response deficit in adult KO mice. This indicates that although Fmrp is dispensable at the initial steps of startle response development, it is necessary for the full development of the response.

Acoustic Stimulation↗

PubMed2004

Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia.

Facial abnormalities in human SHH mutants have implicated the Hedgehog (Hh) pathway in craniofacial development, but early defects in mouse Shh mutants have precluded the experimental analysis of this phenotype. Here, we removed Hh-responsiveness specifically in neural crest cells (NCCs), the multipotent cell type that gives rise to much of the skeleton and connective tissue of the head. In these mutants, many of the NCC-derived skeletal and nonskeletal components are missing, but the NCC-derived neuronal cell types are unaffected. Although the initial formation of branchial arches (BAs) is normal, expression of several Fox genes, specific targets of Hh signaling in cranial NCCs, is lost in the mutant. The spatially restricted expression of Fox genes suggests that they may play an important role in BA patterning. Removing Hh signaling in NCCs also leads to increased apoptosis and decreased cell proliferation in the BAs, which results in facial truncation that is evident by embryonic day 11.5 (E11.5). Together, our results demonstrate that Hh signaling in NCCs is essential for normal patterning and growth of the face. Further, our analysis of Shh-Fox gene regulatory interactions leads us to propose that Fox genes mediate the action of Shh in facial development.

Animals↗

PubMed2003

Immunolocalization of Zic2 expression in the developing mouse forebrain.

The Zic genes are a family of zinc finger transcription factors defined by their homology with the Drosophila gene, odd-paired (opa). Zic2 has a critical role in forebrain development, as is evidenced by the fact that, in both mice and humans, diminished expression results in the severe forebrain malformation known as holoprosencephaly. Published information indicates that Zic2 expression is most prominent in the dorsal neural tube/spinal cord and in the hindbrain; however, there is no published description of the pattern of expression of Zic2 in the developing forebrain where the main Zic2 associated phenotype occurs. Using a Zic2-specific antiserum, we present new information about the expression of Zic2 in the developing mouse forebrain. In addition, we show that in sonic hedgehog (Shh) null mice, the expression of Zic2 is expanded ventrally in some structures while absent in others, suggesting that Shh has a role in regulating the expression of Zic2.

Animals↗

PubMed2002

Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.

Animals↗