06-P023

– Withdrawn

06-P024

Identification of Lmnb1 as a possible modifier gene for neural

tube defects in the mouse

Sandra Castro1, Kit-Yi Leung1, Dawn Savery1, Peter Gustavsson2,

Andrew J. Copp1, Nicholas D.E. Greene1

1UCL Institute of Child Health, London, United Kingdom2Karolinska University Hospital, Stockholm, Sweden

Neural tube defects (NTDs), such as spina bifida and anen-

cephaly, are severe birth defects which result from failure of clo-

sure of the neural tube (the precursor of the brain and the spinal

cord). In humans, NTDs affect 1 per 1000 pregnancies, with mul-

tifactorial aetiology suggestive of a combination of one or more

genetic factors with contribution from environmental risk fac-

tors. The curly tail (ct/ct) mouse represents an established model

for NTDs; affected embryos develop spina bifida which closely

resembles the corresponding birth defects in humans both in

terms of pathology and multifactorial etiology. The major genetic

defect in curly tail is a regulatory mutation that results in reduced

expression of grainyhead-like-3 (Grhl3). We identified a putative

regulatory mutation in the Grhl3 gene, and showed by transgenic

BAC rescue that increased expression of Grhl3 prevents NTDs in

ct/ct embryos. However, the penetrance is strongly influenced

by, as yet unidentified modifier genes. In the course of proteomic

analysis of curly tail we identified differences in the migration of

lamin B1 on 2D gels, between samples from ct/ct embryos and a

closely matched wild-type strain. Migration differences have been

found to result from a genomic polymorphism that results in var-

iation in protein sequence. Analysis of sub-strains of mice carry-

ing different combinations of the laminB1 polymorphism and the

Grhl3 mutation suggest that Lmnb1 could potentially act as a

modifier of NTD risk in curly tail mice.

doi:10.1016/j.mod.2009.06.250

06-P025

Rspo2 in laryngeal patterning

Sheila Bell, Jeffrey Whitsett

Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United

States

Rspo2 is a secreted agonist of the canonical Wnt signaling

pathway that signals through Lrp6 invitro and invivo. Rspo2 defi-

cient murine fetuses die at birth and exhibit a variety of malfor-

mations including tracheal and laryngeal cartilage defects, cleft

palate, reduced lung size, and limb reduction defects. Further

invivo studies have revealed that Rspo2 signaling is also mediated

through the Lrp5 receptor. The combined absence of Rspo2 and

Lrp5 or Lrp6 results in an impairment in lung branching morpho-

genesis resulting in a lung that is normally patterned along the

proximal distal axis but possesses hyper-dilated proximal air-

ways. Rspo2/Lrp5/Lrp6+/ individuals fail to form any tracheal carti-

lage rings, form only rudiments of the cricoid and arytenoid

cartilages, are athymic, and have micromandibles frequently

accompanied by a cleft upper lip. More than 50% of the fetuses

also possessed complete tracheal esophageal fistulas originating

cranially at the level of the arytenoid cartilages. These findings

indicate that Rspo2 signaling plays a role not only in lung branch-

ing morphogenesis but also separation of the trachea and

esophagus.

doi:10.1016/j.mod.2009.06.251

06-P026

Morphological and morphometric analyses of rats fetuses

exposed to antiepileptic drugs

Giuliano Ciambelli, Mariana Perez, Marco Aurlio Candella, Juliana

Bassi, Maria Beatriz Beraldo, Rodrigo Bastos, Suzana Moraes

Pontific Catholic University of So Paulo, Sorocaba/ So Paulo, Brazil

Background: It is estimated that 1/3 of the epilepsy patients are

in fertile age, and that 1 out of 250 pregnant women are exposed

to antiepileptic, which requires experimental models of teratoge-

nicity. Objective: To compare the teratogenic effect of valproic acid

(VPA), carbamazepine (CARB) and lamotrigine (LAMO) in rat

fetuses. Methods: Wistar rats were treated with AV, CARB and

LAMO (200 or 400 mg/kg) on days 8th or 11th of gestation (groups

1–6); with distilled water (groups 7 and 8, sham) and no treated

(group 9, control). The fetuses were weighted, measured and

assessed macroscopically for the presence of congenital malfor-

mations. The placenta was also weighted. Results: All treated

groups on day 11th of gestation had the fetal weight, fetal length

and placental weight lower than the control and sham groups

(p < 0,01 to p < 0,05). The omphalocele had a higher incidence with

VPA on 11th day and CARB on the 8th and 11th days of pregnancy.

The micrognathia was representative in all treated groups except

VPA on 8th day and CARB 200 mg/kg. The medial cleft lip was

found only with LAMO. The low implantation of the ear was more

incident with 400 mg/kg of VPA on the 11th day, while the short

tail was observed with CARB 400 mg/kg, regardless of the gesta-

tion day. The clinodactyly was predominant with LAMO 200 mg/

kg, regardless of the day, and 400 mg/kg on the 8th day. Conclusion:

All antiepileptics studied are teratogenic, with particular empha-

sis on the VPA.

doi:10.1016/j.mod.2009.06.252

06-P027

Compensatory role of nectin-1 and -3 in the epidermal homeo-

stasis and hair formation

Toshiyuki Yoshida1, Jun Miyoshi2, Yoshimi Takai3, Irma Thesleff1

1Institute of Biotechnology, University of Helsinki, Helsinki, Finland2Department of Molecular Biology, Osaka Medical Center for Cancer and

Cardiovascular Diseases, Osaka, Japan3Department of Molecular and Cellular Biology, Kobe University Grad-

uate School of Medicine, Kobe, Japan

Nectins are immunoglobulin-like cell adhesion proteins which

function in cell–cell junctions and contacts. Mutations in the

S127M E C H A N I S M S O F D E V E L O P M E N T 1 2 6 ( 2 0 0 9 ) S 1 2 0 – S 1 3 6