Conf férencie er - Centre de recherche du CHU de Québec

Confférencieer
Dr Nicollas Pilon
n
Professeuur adjoint
Départem
ment des ssciences b
biologiquees
Faculté ddes sciencees, UQÀM
M
Courriel: [email protected]
Invité paar Dre Lu
ucie Jean
nnotte
Titre: La généétique mo
oléculairee du dévveloppem
ment applliquée au
ux
ocristopatthies: lee cas particuliier de la maaladie de
d
neuro
Hirscchsprung
Backgrou
und: Neural crest cells (N
NCC) are a ttransient miggratory cell ppopulation thaat generates
diverse cell types su
uch as neuro
ons and gliaa of the enteeric nervous system (EN
NS). Via an
insertion
nal mutation screen
s
for locci affecting N
NCC developm
ment in mice, we identifiedd one line –
named TashT
T
– that displays
d
a paartially penetrrant aganglionnic megacoloon phenotype in a strong
male-biaased manner.. This phenotype is rem
miniscent off human Hirrschsprung’s disease, a
neurocrisstopathy with
h a still unexp
plained male ssex bias.
Methodo
ology/Principaal Findings: In
I contrast too the megacolon phenotyppe, colonic agganglionosis
is almostt fully penetrrant in TashTTg/Tg animaals. The sex bbias in megaccolon expressiivity can be
explained by the factt that the malle ENS ends,, on average, around a “tiipping point” acting as a
threshold
d-like level off minimal collonic ganglioonosis while thhe female EN
NS ends, on aaverage, just
beyond it. Detailed analysis of embryonic gguts revealedd that agangllionosis in T
TashTTg/Tg
animals is
i due to slow
wer migration
n of enteric NC
CC. The TashhT insertional mutation is localized in
a gene desert
d
contain
ning multiple highly consserved elemennts that exhibbit repressivee activity in
reporter assays. RNA
Aseq analysess and 3C assaays revealed that the TashhT insertion results in a
NCC-speecific relief of
o repression of the novel gene Fam1662b, which enncodes a trannsmembrane
protein of
o unknown function.
f
Thee transcriptionnal signature of TashTTgg/Tg enteric N
NCC is also
notably characterized
d by the down
nregulation oof several X-llinked genes and the upreegulation of
g secreted pro
oteins – incluuding Gdnf aand Edn3, whhich encode key ligands
many geenes encoding
normally
y produced by
y the gut meseenchyme.
Conclusiions/Significaance: The TasshT mouse liine is the firsst model repoorted to truly recapitulate
the malee sex bias of Hirschspru
ung’s disease and also alllowed the iddentification of a novel
candidate locus for th
his neurocristtopathy. Thiss work furtheer identified a threshold-like level of
ENS leng
gth beyond which
w
aganglio
onosis is funcctionally tolerrated.
Lund
di le 26 m
mai 20144, 11:30
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