PAUL E. NEUMANN, M.D.
Email: paul.neumann@dal.ca

Developmental Neurogenetics

This laboratory uses genetic and morphologic methods to study genetic influences on development of the mammalian central nervous system. In particular, we are interested in genes involved in the etiology of nervous system malformation, e.g., neural tube defects, and genes that are responsible for variation in pattern formation during development of the brain. Pattern formation underlies the phylogenetic and ontogenetic development of complex functions of the human brain. Three experimental mammalian (mouse) systems are currently being investigated in this laboratory: cerebellar folial pattern, the " barrelfield " in the somatosensory cortex and hypothalamic morphology.

1. Cerebellar folial (or fissure) pattern varies between inbred strains of mice as a multifactorial trait. We have mapped three loci ( Cfp1 and Cfp5 on Chromosome 4, and Cfp4 on Chromosome 5) that display pattern- or fissure-specific effects, in contrast to other genetic factors ( Cfp2 and Cfp3 ) that have general influences on fissure number. In collaboration with Dr. Melanie Dobson, we are attempting to isolate the Cfp1 , Cfp4 and Cfp5 loci by candidate gene analysis and positional cloning strategies.

2. The barrelfield of the somatosensory cortex of mice displays a striking distribution of neurons in layer IV, in which each "barrel" represents a single whisker. The somatosensory cortex of barrelless ( brl ) mutants appears to have relatively randomly arranged neurons with no discernable barrel formation. The brl mutation is an early retrotransposon insertion into the adenylyl cylase type I ( Adcy1 ) gene. The aim of current work is to identify other genes involved in barrel formation.

3. Inbred mice display variation in the nuclear organization of the hypothalamus. C57BL/6J inbred mice lack an accessory magnocellular neurosecretory nucleus called the pars compacta of the medial preoptic nucleus ( MPOpc ). This strain also shows relatively high perinatal mortality and reduced maternal behaviour . In collaboration with Drs. Bruce Mathieson and Richard Brown, we are attempting to identify genes involved in these variants.

Research Support

Medical Research Council

Selected Publications

Neumann PE, Collins RL. Genetic dissection of susceptibility to audiogenic seizures in crosses of inbred mice. Proc Natl Acad Sci USA 1991; 88:5408-5412.

Thomas K, Musci T, Neumann PE , Capecchi M. Swaying is a mutant allele of the proto-oncogene, Wnt-1. Cell 1991; 67:969-976.

Neumann PE , Garretson JD, Skabardonis GP, Mueller GG. Genetic analysis of cerebellar folial pattern in crosses of C57BL/6J and DBA/2J inbred mice. Brain Res 1993; 619:81-88.

Neumann PE, Frankel WN, Letts VA, Coffin JM, Copp AJ, Bernfield M. Multifactorial inheritance of neural tube defects: Localization of the major gene and recognition of modifiers in ct mutant mice. Nature Genetics 1994; 6:357- 362.

Welker E, Armstrong-James M, Bronchti G, Ourednik W, Baechler F, Dubois R, Guernsey DL, Van der Loos H, Neumann PE. Altered sensory processing in somatosensory cortex of the mouse mutant barrelless . Science 1996; 271:1864- 1867.

Greer WL, Riddell DC, Byer DM, Welch JP, Girouard GS, Sparrow SM, Gillan TL, Neumann PE. Linkage of Niemann -Pick Disease Type D to the same region of human chromosome 18 as Niemann -Pick Disease Type C. Am J Human Genet 1997; 61:139-142.

Gupta SK , De Becker I, Guernsey DL, Neumann PE . PCR-based assessment for Wilms ' tumor in sporadic aniridia . Am J Ophthalmol 1998; 125:687- 692.

Abdel-Majid RM, Leong WL, Schalkwyk LC, Smallman DS, Wong ST , Storm DR, Fine A, Dobson MJ, Guernsey DL, Neumann PE . Loss of adenylyl cyclase I activity disrupts patterning of mouse somatosensory cortex. Nature Genetics 1998; 19:289-291.

Gupta SK , DeBecker I, Tremblay F, Guernsey DL, Neumann PE . Genotype-phenotype correlations in aniridia . Am J Ophthalmol 1998; 126:203- 210.

Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE. The Nova Scotia (type D) form of Niemann -Pick disease is caused by a G3097 to T transversion in NPC1. Am J Human Genet 1998; 63:52-54.

Brown RE, Mathieson WB, Stapleton J, Neumann PE .   Maternal behavior in C57BL/6J and DBA/2J inbred mice.  Physiology & Behavior 1999; 67:599-605.

Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE.   NPC1 mutations highlight a conserved cysteine -rich domain.  Am J Human Genetics 1999; 65:1252-1260.

Beresford RG, Tatlidil C, Riddell DC, Welch JP, Ludman MD, Neumann PE, Greer WL.  Absence of fragile X syndrome in Nova Scotia .   J Med Genet 2000; 37:77-9.

Leong WL, Dobson MJ, Logsdon JM Jr., Abdel-Majid RM, Schalkwyk LC, Guernsey DL, Neumann PE . ETn Insertion in the mouse Adcy1 gene: transcriptional and phylogenetic analyses.  Mamm Genome 2000; 11:97-103.

Mathieson WB, Taylor SW, Marshall M, Neumann PE .  Strain and sex differences in the morphology of the medial preoptic nucleus of mice. J Comp Neurol 2000; 428:254-265.