Hedgehog controls neural stem cells through p53-independent regulation of Nanog.
Hedgehog (Hh) pathway has a pivotal function in development and tumorigenesis, processes sustained by stem cells (SCs). The transcription factor Nanog controls stemness acting as a key determinant of both embryonic SC self-renewal and differentiated somatic cells reprogramming to pluripotency, in concert with the loss of the oncosuppressor p53. How Nanog is regulated by microenvironmental signals in postnatal SC niches has been poorly investigated. Here, we show that Nanog is highly expressed in SCs from postnatal cerebellum and medulloblastoma, and acts as a critical mediator of Hh-driven self-renewal. Indeed, the downstream effectors of Hh activity, Gli1 and Gli2, bind to Nanog-specific cis-regulatory sequences both in mouse and human SCs. Loss of p53, a key event promoting cell stemness, activates Hh signalling, thereby contributing to Nanog upregulation. Conversely, Hh downregulates p53 but does not require p53 to control Nanog. Our data reveal a mechanism for the function of Hh in the control of stemness that represents a crucial component of an integrated circuitry determining cell fate decision and involved in the maintenance of cancer SCs.
Po
Agnese
A
Department of Experimental Medicine, Sapienza University, Rome, Italy.
Ferretti
Elisabetta
E
Miele
Evelina
E
De Smaele
Enrico
E
Paganelli
Arianna
A
Canettieri
Gianluca
G
Coni
Sonia
S
Di Marcotullio
Lucia
L
Biffoni
Mauro
M
Massimi
Luca
L
Di Rocco
Concezio
C
Screpanti
Isabella
I
Gulino
Alberto
A
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D015513:Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000071676:Zinc Finger Protein GLI1