• No results found

The  FoxF2  Gene  in  Development  and  Disease

N/A
N/A
Protected

Academic year: 2021

Share "The  FoxF2  Gene  in  Development  and  Disease"

Copied!
2
0
0

Loading.... (view fulltext now)

Full text

(1)

The  FoxF2  Gene  in  Development  and  Disease  

 

Akademisk  avhandling    

för  avläggande  av  filosofie  doktorexamen  i  Naturvetenskap,  inriktning  genetik,  som   kommer  att  offentligt  försvaras  i  föreläsningssal  Ragnar  Sandberg,  medicinaregatan  7A  

Göteborg,  torsdagen  den  26  november,  2015,  kl.  10:00    

av     Azadeh  Reyahi  

 

Faculty  opponent:  

Prof.  Vladimir  Kalinichenko,  

Department  of  Pediatrics,  College  of  Medicine  of  the  University  of  Cincinnati,   Ohio,  USA  

   

This  thesis  is  based  on  the  following  publications,  referred  to  by  roman   numerals  in  the  text:  

 

I.   Foxf2   is   required   for   brain   pericyte   differentiation   and   development   and   maintenance  of  the  blood-­‐brain  barrier    

Reyahi  A,  Nik  AM,  Ghimai  M,  Gritli-­‐Linde  A,  Pontén  F,  Johansson  BR,  Carlsson  P.    

Developmental  Cell  (2015)  34,  19-­‐23.    

 

II.  FOXF2,  a  novel  risk  locus  for  stroke  and  small  artery  disease    

Ganesh  Chauhan,  Corey  R  Arnold,  Audrey  Y  Chu,  Myriam  Fornage,  Azadeh  Reyahi,  Joshua   C  Bis,  Aki  S  Havulinna  (equal  contribution  first  authors)  ...  additional  co-­‐authors  excluded   for   brevity...   (joint   senior  authors:)   Lenore   J   Launer,   M   Arfan   Ikram,   Peter   Carlsson,   Daniel   I   Chasman,   Sarah   J   Childs,   William   T   Longstreth,   Jr,   Sudha   Seshadri,   Stéphanie   Debette.    

Submitted      

III.   Foxf2   in   intestinal   fibroblasts   reduces   numbers   of   Lgr5(+)   stem   cells   and   adenoma  formation  by  inhibiting  Wnt  signaling    

Nik  AM,  Reyahi  A,  Pontén  F,  Carlsson  P.    

Gastroenterology  (2013)  144(5),  1001-­‐11.    

 

IV.  Foxf2  enhances  Tgfβ  signaling  in  secondary  palate  development    

Ali  M.Nik,  Jeanette  Astroga-­‐Johansson,  Azadeh  Reyahi,  Mozhgan  Ghiami,  Fredrik  Pontén   and  Peter  Carlsson.    

Manuscript      

 

(2)

The  Foxf2  gene  in  development  and  disease  

 

Azadeh Reyahi

Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, SE 405 30, Göteborg, Sweden

  Abstract

In  this  thesis  I  present  our  recent  data  on  the  involvement  and  the  mechanism  of   action   of   the   forkhead   transcription   factor   Foxf2   in   development   of   the   brain   microvasculature,  formation  of  the  blood-­‐brain  barrier,  control  of  the  intestinal   stem  cell  niche,  and  fusion  of  the  secondary  palate.  The  potential  clinical  signifi-­‐

cance  of  these  findings  is   strengthened   by   a   correlation   between   Foxf2   expres-­‐

sion  and  intestinal  adenoma  formation,  and  by  association  between  genetic  vari-­‐

ants  in  human  FOXF2  and  incident  stroke.  

We  showed  that  Foxf2  is  expressed  in  brain  pericytes,  but  not  in  mural  cells  of   other   organs.   Foxf2   null   mutants   have   a   defective   brain   vasculature   and   suffer   from   intracranial   hemorrhage   and   a   leaky   blood-­‐brain   barrier   with   increased   endothelial  vesicular  trans-­‐cytosis.  Foxf2-­‐/-­‐  brain  pericytes  have  diminished  Pdg-­‐

frβ  expression,  and  the  cerebral  vasculature  a  reduced  activity  of  the  Tgfβ  –Alk5–

Smad2/3  signaling  pathway,  associated  with  decreased  expression  of  integrins,   Tgfb2,  Tgfbr2,  Alk5  and  other  pathway  components.    

In   a   large   GWAS   performed   by   an   international   consortium,   we   identified   a   genome-­‐wide  significant  association  of  common  variants  near  FOXF2  with  risk  of   stroke.  Conditional  knockout  mice,  in  which  Foxf2  was  deleted  in  healthy  adults,   developed  clinical  signs  of  stroke  and  exhibited  cerebral  ischemia,  reactive  glio-­‐

sis  and  microhemorrhage.  The  animal  model  results  thus  corroborate  the  human   genetic  association  and  identifies  FOXF2  as  a  novel  risk  locus  for  stroke.  

In  the  intestine  we  showed  that  Foxf2  is  expressed  by  subepithelial  fibroblasts   and  restricts  the  size  of  the  stem  cell  niche,  and  thereby  the  number  and  prolif-­‐

eration  of  Lgr5+  stem  cells.  Foxf2  is  a  target  of  epithelial  hedegehog  signaling  and   inhibits  the  Wnt  pathway  by  increasing  the  expression  of  the  extracellular  Wnt   inhibitor   Sfrp1.   As   a   consequence,   reduced   Foxf2   expression   significantly   in-­‐

creases  both  initiation  and  growth  of  intestinal  tumors.    

Reduced   proliferation   and   decreased   extracellular   matrix   production   in   the   neural  crest-­‐derived  mesenchyme  of  the  palatal  shelves  was  found  to  be  respon-­‐

sible   for   the   cleft   palate   phenotype   in   Foxf2   null   mutants.   Mechanistically,   the   defect  is  associated  with  reduced  canonical  Tgfβ  signaling  and  integrin  expres-­‐

sion.   The   Tgfb2   mRNA   level   was   not   affected,   but   the   amount   of   Tgfβ2   protein   was  significantly  decreased  in  mutant  palatal  shelf  mesenchyme.  

 

Keywords:  Foxf2,  Pericyte,  Pdgfrβ,  Blood-­‐brain  barrier,  Stroke,  Wnt  signaling,   sFRP-­‐1,  Intestinal  stem  cell  niche,  Lgr5,  Palatogenesis,  Cleft  palate,  Tgfβ  signaling   ISBN  978-91-628-9634-8

References

Related documents

Gene expression of Quaking in sporadic Alzheimer's disease patients is both upregulated and related to expression levels of genes involved in amyloid plaque and neurofibrillary

För att uppskatta den totala effekten av reformerna måste dock hänsyn tas till såväl samt- liga priseffekter som sammansättningseffekter, till följd av ökad försäljningsandel

Inom ramen för uppdraget att utforma ett utvärderingsupplägg har Tillväxtanalys också gett HUI Research i uppdrag att genomföra en kartläggning av vilka

a) Inom den regionala utvecklingen betonas allt oftare betydelsen av de kvalitativa faktorerna och kunnandet. En kvalitativ faktor är samarbetet mellan de olika

It reads data stored in commonly used formats (EMBL, Genbank, BLAST and Mauve outputs) or in user-created tabular files and allows comparisons of one or several subsegments of

A simplified commonly accepted model for Pol II transcription can be outlined as follows: (1) recruitment of unphosphorylated Pol II to the promoter followed by (2) Pol II

The 11 integrin chain is present in the corneal stroma early in human fetal development, it is scarce in the normal adult cornea and it appears to be upregulated in the

Foxf2 in regulation of the intestinal stem cell niche and adenoma formation (Paper III)