Prokineticin 2 in Olfactory Bulb Neurogenesis and Neuronal Control of Reproduction
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Transcript of Prokineticin 2 in Olfactory Bulb Neurogenesis and Neuronal Control of Reproduction
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Prokineticin 2 in Olfactory Bulb Neurogenesis and Neuronal Control of
Reproduction
Chengkang (CK) ZHANG PhD
Dept of PharmacologyUniversity of California - Irvine
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Prokineticins
• PK1/EG-VEGF and PK2 are ~10KDa cysteine-rich secreted proteins• Binds to two G-Protein Coupled Receptors: PKR1 and PKR2• PK1 and PK2 involved in diverse biological processes.
– GI motility (PK1), circadian rhythms (PK2), endocrine tissue angiogenesis (PK1), tumor angiogenesis (PK2) and pain sensitization (PK1, PK2), and neurogenesis (PK2)
Prokineticin 1Prokineticin 2
Frog Bv8Snake MIT1
CERDVQCGGATCCAISLWLRGLRMCTPLGREGEECHPGCDKDSQCGGGMCCAVSIWVKSIRICTPMGKLGDSCHPLCDKDVQCGSGTCCAASAWSRNIRFCIPLGNSGEDCHPACERDLQCGKGTCCAVSLWIKSVRVCTPVGTSGEDCHPA* * ** * *
SHKVPFFRKRKHHTCPCLPNLLCSRFPDGRYRCSMDLKNINFTRKVPFFGRRMHHTCPCLPGLACLRTSFNRFICLAQKSHKVPYDGKRLSSLCPCKSGLTCSK.SGEKFKCSSHKIPFSGQRMHHTCPCAPNLACVQTSPKKFKCLSKS
MRGATRVSIMLLLVTVSDCMRSLCCAPLLLLLLLPPLLLTPPAGDA
MKCFAQIVVLLLVIAFSHG
signaling peptide
AVITGAAVITGAAVITGAAVITGA
* * * *
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Proliferation of neural stem cells
Neuronal Progenitors
Differentiationinto
Immature neurons
Migration to
Final location
Integration into a
Neural circuit
Maturation to a fully functional
neuron
Neurogenesis in adult mammalian brain
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PKR2
/ G
FAP
PKR2
/ P
SA-N
CAM
PKR2
/ P
SA-N
CAM
PK2
Reciprocal expression patterns of PK2 and its receptor PKR2 in
SVZ-OB
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Control PK2 PK2 + A1MPK1
Migration of Neuronal Progenitors towards PK2 Migration blocked by PK2 Antagonist: A1MPK1 PK2 increased motility of NPC
Chemoattractive effect of PK2 on neuronal progenitors
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PK2 promotes the neuronal differentiation of neural progenitors
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Defects in OB development of PK2-/- mice
WT OB KO OB WT PG WT PG0
20
40
60
80
100
*
*Brd
U P
os
tive
Ce
lls(p
er
mm
2)↑Cell Death
WT KO WT pg KO pg0
10
20
30
40 *
**TU
NE
L P
ost
ive
Cel
ls(p
er
mm
2)
↓Cell migration
WT
KO
WT KO
↓OB size
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bHLH proneural factors and PK2 in the OB
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Ngn1 and MASH1 activate PK2 expression by binding to E-boxes on PK2 promoter
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Summary• PKR2 is expressed in neuronal progenitors from the SVZ
• PK2 acts as a chemoattractant for neuronal progenitors
• PK2 promotes neuronal differentiation of NPC
• PK2 -/- mice have severe defect in OB development
• PK2 is a functional target gene of bHLH factors for OB development
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Mutations in PK2 and PKR2 genes as new etiology for Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic
hypogonadism (IHH)
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Hypoplasia of the reproductive organs in Pk2-/- mice
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Gonadotropin-releasing hormone (GnRH) regulates the hypothalamo-pituitary-gonadal (HPG) axis in all vertebrates studied. GnRH neurons that regulate the HPG axis are primarily derived from progenitor cells in the nasal compartment (NC) and migrate along olfactory system derived fibers across the cribriform plate to destinations in the forebrain
MCE, (2001), 173-184
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Abnormality of the GnRH neurons in Pk2-/- mice
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GnRH neuron does not express PKR2
A. B. C.
D. E. F.
G. H. I.
PKR2 GnRH Merge
E13.5VNO
E13.5 Basal Forebrain
AdultPreoptic Area
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A. B. C. D.
E. F. G. H.
Defect of GnRH neuron migration in embryonic Pk2-/- mice
E16.5 Pk2+/+
E16.5 Pk2-/-
Nasal Septum OB MPO ME
OB
OB
*
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PK2 gene mutations in KS and nIHH patients
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PKR2 gene mutations in KS and nIHH patients
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Acknowledgements
Zhou Lab• Michelle Y. Cheng• Roy Jia-Da Li• Kwan Ng• Kate Burton• Wang-Ping Hu• Alex Lee• Chong-Wei Wen
Collaborators• Bill Crowley (MGH)• Nelly Pettiloud (MGH)• Pam Mellon (UCSD)
• Yi Sun (UCLA)• Michael E. Greenberg (HMS)• David Anderson (Caltech)