Target type: biologicalprocess
The multiplication or reproduction of neuroblasts that will give rise to granule cells. A granule cell is a glutamatergic interneuron found in the cerebellar cortex. [GO_REF:0000021, GOC:cls, GOC:dgh, GOC:dph, GOC:jid, PMID:15157725]
Cerebellar granule cell precursor proliferation is a fundamental process in the development of the cerebellum, the brain region responsible for motor coordination, balance, and learning. This process involves a complex interplay of molecular signals and cellular interactions that drive the expansion of a specific population of neural progenitors, known as cerebellar granule cell precursors (GCPs).
GCPs are generated in the external granular layer (EGL) of the cerebellum, a transient structure that serves as the birthplace of these cells. The proliferation of GCPs is highly regulated and influenced by several key factors, including:
**1. Sonic Hedgehog (Shh) Signaling:** Shh is a secreted signaling molecule that plays a crucial role in initiating and maintaining GCP proliferation. Shh is expressed in the Purkinje cells, a layer of neurons located beneath the EGL. Shh signals to GCPs through a complex pathway involving the Patched (Ptch) and Smoothened (Smo) receptors. This signaling pathway activates transcription factors like Gli1 and Gli2, which promote GCP proliferation.
**2. Wnt Signaling:** Wnt proteins are another family of secreted signaling molecules that regulate various aspects of cerebellar development, including GCP proliferation. Wnt signaling promotes GCP proliferation through activation of the β-catenin pathway, leading to increased expression of genes involved in cell cycle progression.
**3. Neurotrophic Factors:** Neurotrophic factors, such as BDNF and NT-3, are secreted proteins that support the survival and proliferation of GCPs. These factors bind to specific receptors on the surface of GCPs, activating intracellular signaling cascades that promote cell growth and survival.
**4. Cell Cycle Regulation:** The proliferation of GCPs is tightly controlled by cell cycle regulators, including cyclins and cyclin-dependent kinases (CDKs). These proteins orchestrate the progression through the cell cycle phases, ensuring that cells divide appropriately.
**5. Extracellular Matrix (ECM):** The ECM provides structural support and signaling cues to GCPs. Specific components of the ECM, such as laminin and collagen, are crucial for GCP adhesion, migration, and proliferation.
**6. Transcription Factors:** Transcription factors, such as Pax6, Math1, and Tbr1, regulate the expression of genes involved in GCP proliferation and differentiation. They act as molecular switches that control the fate and behavior of these cells.
The proliferation of GCPs is a dynamic process that involves a complex interplay of these factors. Dysregulation of any of these signaling pathways or molecular regulators can lead to developmental defects in the cerebellum, resulting in neurological disorders such as ataxia and autism.
Understanding the molecular mechanisms underlying GCP proliferation is crucial for developing novel therapeutic strategies for neurological disorders.
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Protein | Definition | Taxonomy |
---|---|---|
Sonic hedgehog protein | A sonic hedgehog protein that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q15465] | Homo sapiens (human) |
Nuclear receptor ROR-alpha | A nuclear receptor ROR-alpha that is encoded in the genome of human. [PRO:DNx, UniProtKB:P35398] | Homo sapiens (human) |
Fibroblast growth factor 2 | A fibroblast growth factor 2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P09038] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
jervine | jervine: teratogen from Veratrum grandiflorum; RN given refers to parent cpd(3beta,23beta)-isomer; structure | piperidines | |
cyclopamine | piperidines | glioma-associated oncogene inhibitor | |
tretinoin | all-trans-retinoic acid : A retinoic acid in which all four exocyclic double bonds have E- (trans-) geometry. retinoic acid : A retinoid consisting of 3,7-dimethylnona-2,4,6,8-tetraenoic acid substituted at position 9 by a 2,6,6-trimethylcyclohex-1-en-1-yl group (geometry of the four exocyclic double bonds is not specified). Tretinoin: An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE). | retinoic acid; vitamin A | anti-inflammatory agent; antineoplastic agent; antioxidant; AP-1 antagonist; human metabolite; keratolytic drug; retinoic acid receptor agonist; retinoid X receptor agonist; signalling molecule |
t0901317 | T0901317: an LXRalpha and LXRbeta agonist | ||
2-[[2-[2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-2-oxoethyl]-1-oxo-5-isoquinolinyl]oxy]propanoic acid ethyl ester | isoquinolines | ||
tivozanib | N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N'-(5-methyl-3-isoxazolyl)urea: KNR-951 is the HCl, monohydrate salt; an antineoplastic agent; structure in first source | aromatic ether | |
cur 61414 | CUR 61414: inhibits the hedehog signaling pathway; structure in first source | ||
2-(5-butoxy-1-oxo-2-isoquinolinyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide | isoquinolines | ||
gdc 0449 | HhAntag691: inhibits the hedgehog pathway and ABC transporters; has antineoplastic activity | benzamides; monochlorobenzenes; pyridines; sulfone | antineoplastic agent; Hedgehog signaling pathway inhibitor; SMO receptor antagonist; teratogenic agent |
robotnikinin | robotnikinin: binds sonic hedgehog protein to block its signaling pathway; structure in first source | ||
sr1001 | SR1001: a selective RORalpha and RORgamma inverse agonist; structure in first source | sulfonamide | |
phosphomannopentaose sulfate | phosphomannopentaose sulfate: structure in first source | ||
pg 545 | PG 545: an anti-angiogenesis agent with heparanase inhibitory activity; structure in first source |