Paul E. Neumann

Swaying is a mutant allele of the proto-oncogene Wnt-1

Mice homozygous for the recessive mutation swaying (sw) are characterized by ataxia and hypertonia, attributed to the malformation of anterior regions of the cerebellum. We show that sw is a deletion of a single base pair from the proto-oncogene Wnt-1. The deletion is predicted to cause premature termination of translation, eliminating the carboxy-terminal half of the Wnt-1 protein. Histological examination shows that sw is phenotypically identical to a previously described wnt-1 mutation introduced into mice by gene targeting. Although both mutations in Wnt-1 disrupt primarily the development of the anterior cerebellum, they also exhibit a variability in expressivity such that rostrally adjacent structures in the midbrain and caudally adjacent structures in the posterior cerebellum can also be affected.

New approaches to catheter navigation for interventional radiology simulation

For over 20 years, interventional methods have improved the outcomes of patients with cardiovascular disease. However, these procedures require an intricate combination of visual and tactile feedback and extensive training. In this paper, we describe a series of novel approaches that have led to the development of a high-fidelity simulation system for interventional neuroradiology. In particular, we focus on a new approach for real-time deformation of devices such as catheters and guidewires during navigation inside complex vascular networks. This approach combines a real-time incremental Finite Element Model (FEM), an optimization strategy based on substructure decomposition, and a new method for handling collision response in situations where the number of contact points is very large. We also briefly describe other aspects of the simulation system, from patient-specific segmentation to the simulation of contrast agent propagation and fast volume-rendering techniques for generating synthetic X-ray images in real time. Although currently targeted at stroke therapy, our results are applicable to the simulation of any interventional radiology procedure.

Inference in linkage analysis of multifactorial traits using recombinant inbred strains of mice

Recombinant inbred strains have been shown to be important tools for segregation and linkage analysis of multifactorial traits. Tests of association have been used as robust methods of linkage detection, however, guidelines for forming inferences from significance levels have not been generally available. In this paper, lessons learned from a Bayesian statistical approach to linkage analysis of Mendelian traits have been applied to studies of multifactorial traits. Criteria for detection of linkage based on Bonferronis correction for multiple testing are also discussed.

Analysis of the hotfoot (ho) locus by creation of an insertional mutation in a transgenic mouse

Hotfoot (ho) mutation is a recessive trait in mice, characterized by motor disorder and male sterility, that maps to chromosome 6. We have identified a transgenic mouse pedigree with a similar trait. Using genetic and molecular approaches, we have demonstrated that the foreign DNA element is located in or near the ho locus. This new allele, designated hoJwg and presumably created by insertional mutagenesis, should make it possible to clone the ho gene. Male infertility in hoJwg male homozygotes was determined to be due to inability of sperm to penetrate the zona pellucida. This was demonstrated by rescuing mutant males by a new technique of gamete micromanipulation, zona pellucida drilling. These findings show that zona drilling is useful both for analysis and preservation of animals with reduced male fertility.

Genetic analysis of cerebellar folial pattern in crosses of C57BL/6J and DBA/2J inbred mice

Variation in the cerebellar folial pattern of mice is influenced by genetic elements [Inouye, M. and Oda, S., J. Comp. Neurol., 190 (1980) 357-362]. In crosses of C57BL/6J and DBA/2J inbred mice, the presence or absence of a specific fissure, the intraculminate fissure, is largely determined by a single genetic locus (Cfp-1), which is located on distal Chromosome 4 [Neumann et al., Brain Res., 524 (1990) 85-89]. In the present study, the mid-sagittal cerebellar folial pattern has been examined in crosses of C57BL/6J and DBA/2J mice and in BXD recombinant inbred strains. At least three loci, including Cfp-1, are involved in variation in vermian pattern formation. Genetic variation in thyroid hormone function may be involved in the inheritance of folial pattern. A locus (Cfp-2) that appears to be partially responsible for this negative genetic correlation in mice may be linked to Afp on Chromosome 5. This hypothesis was suggested by the negative correlation between neonatal serum T4 level and the number of folia in rats given neonatal injections of thyroxine or propylthiouracil [Lauder, J.M. et al., Brain Res., 76 (1974) 33-40].

Confirmation of the influence of a chromosome 7 locus on susceptibility to audiogenic seizures.

Mouse strain differences in susceptibility to audiogenic seizures (AGS) are due to allelic differences at multiple genetic loci. Three loci that influence susceptibility to AGS have been mapped on Chromosomes (Chr) 12, 4, and 7 (Asp-1, Asp-2, and Asp-3, respectively). Here we report evidence that confirms linkage of Asp-3 to c on Chr 7 and parental effects on AGS susceptibility, but not genomic imprinting of Asp-3.

Genetic and behavioral tests of the McManus hypothesis relating response to selection for lateralization of handedness in mice to degree of heterozygosity.

McManus advanced a genetic hypothesis to explain differences of lateralization between HI and LO lines of mice selectively bred for degree of handedness. It states that lateralization is a function of heterozygosity. Specifically it predicts that (a) the HI line will be more heterozygous than the LO line and (b) populations with a greater average heterozygosity (AH) will be more strongly lateralized. Both genetic and behavioral preheterozygosity (AH) will be more strongly lateralized. Both genetic and behavioral predictions were tested here. Results using coat color and biochemical variants show that AH in the HI line is somewhat less (not greater) than that in the LO line. The handedness of HET control mice and HI by LO reciprocal hybrids, where AH is greater than that of the HI line, exhibits lessened (not greater) lateralization. Results reject the heterozygosity hypothesis. A model for the inheritance of human handedness that accounts, for difficulty in detecting heritable differences in degree of asymmetry is presented.

Further evidence that a mouse Chromosome 4 locus influences cerebellar folial pattern

The cerebellar folial pattern of mice displays marked variation among inbred strains. Previous studies of progeny of crosses of C57BL/6 mice with DBA/2J and BALB/cByJ mice indicated a multifactorial mode of inheritance in both cases. The cross with DBA/2J led to the mapping, to Chromosome 4, of a locus (Cfp-1) that influences the frequency of the intraculminate fissure. Here we report that Cfp-1 influences the frequency of the declival sulcus, and appears to influence the frequency of the intraculminate and precentral fissures, in F2 hybrid offspring from crosses of C57BL/6J and BALB/cByJ mice.

Genetic Contributions to Kindling: An Experimental Approach

The development of kindled seizures has been shown to be influenced by genetic factors. The establishment of kindling-prone and kindling-resistant rat populations through selective breeding, along with the reported variations in kindling rates among inbred strains of mice strongly suggests the contribution of genetics to kindling [2,6,17,18]. The rapid kindling rates of genetically epilepsy prone rats [29] and El mice [13] in comparison with appropriate controls provide additional examples of the influence of genetic factors on kindled seizure development. However, to date, no systematic analysis of these factors has been reported for kindling-induced seizures.