Transforming Growth Factor-α Null and Senescent Mice Show Decreased Neural Progenitor Cell Proliferation in the Forebrain Subependyma

Abstract

The adult mammalian forebrain subependyma contains neural stem cells and their progeny, the constitutively proliferating progenitor cells. Using bromodeoxyuridine labeling to detect mitotically active cells, we demonstrate that the endogenous expression of transforming growth factor-␣ (TGF␣) is necessary for the full proliferation of progenitor cells localized to the dorsolateral corner of the subependyma and the full production of the neuronal progenitors that migrate to the olfactory bulbs. Proliferation of these progenitor cells also is diminished with age (in 23-to 25-months-old compared with 2-to 4-months-old mice), likely because of a lengthening of the cell cycle. Senescence or the absence of endogenous TGF␣ does not affect the numbers of neural stem cells isolated in vitro in the presence of epidermal growth factor. These results suggest that endogenous TGF␣ and the effects of senescence may regulate the proliferation of progenitor cells in the adult subependyma, but that the number of neural stem cells is maintained throughout life.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Targeted and naturally occurring (waved-1) mutations of TGF-α in mice leads to defects in hair follicle and eye development, phenotypes similar to the spontaneous EGFR mutation of the waved-2 mouse [133][134][135]. Similar to EGFR-null mice, TGF-α-knockout mice also show decreased forebrain neural progenitor cell proliferation, although this does not manifest in an obvious behavioral phenotype in the mice [136]. Female mice with combined deficiency of amphiregulin, EGF and TGF-α display diminished mammary gland ductal outgrowth during puberty with severe defects in mammopoeisis and lactogenesis [131].…”

Epigenetic regulation of aging stem cells

“…In the nervous system, the ability of NSCs to produce new neurons (neurogenesis) declines with age (Kuhn et al, 1996;Tropepe et al, 1997;Bondolfi et al, 2004;Enwere et al, 2004;Hattiangady and Shetty, 2008). Instead, aging is accompanied by increased production of astrocytes and elevated expression of astrocytespecific genes in the brain, indicating a loss of multipotentiality of stem/progenitor cells and astroglial lineage skewing (Peinado et al, 1998;Lee et al, 2000;Bondolfi et al, 2004).…”

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

“…Therefore, for neurogenesis to proceed in the adult mouse SVZ, EGFR should be simultaneously activated in proliferating NPCs and inhibited in NPCs that initiate their differentiation to neuroblasts. In physiological conditions, EGFR activation is produced, at least in part, by TGF-a [25], whereas EGFR inhibition occurs by the action of locally produced nitric oxide [41,[60][61][62]. Although the mechanism is not fully understood, the concomitance of the two EGFR states within the SVZ is probably implemented by a specific spatial organization allowing the creation of microdomains where either proliferation or differentiation takes place preferentially, as it has been well documented for the generation of blood cells from hematopoietic precursors in the bone marrow [63].…”

“…EGFR activation controls basic cellular functions, such as proliferation, survival, migration, and differentiation or dedifferentiation [23]. In the normal adult SVZ, EGFR is expressed by nestin-positive NPCs [24], and EGFR activation by endogenous transforming growth factor-a (TGF-a) is necessary for NPC proliferation and neurogenesis [25]. In contrast with its physiological role, experimental EGFR stimulation by intraventricular infusion of EGFR ligands produces an enlargement of the SVZ NPC population, but a preferential differentiation toward glial lineages [26][27][28].…”