Spred1, a negative regulator of Ras–MAPK–ERK, is enriched in CNS germinal zones, dampens NSC proliferation, and maintains ventricular zone structure

Abstract

Neural stem cells (NSCs) have great potential for self-renewal, which must be tightly regulated to generate appropriate cell numbers during development and to prevent tumor formation. The Ras-MAPK-ERK pathway affects mitogen-stimulated proliferation, and negative regulators are likely to be important for keeping selfrenewal in check. Sprouty-related protein with an EVH1 domain (Spred1) is a recently discovered negative Ras-MAPK-ERK regulator linked to a neurofibromatosis 1 (NF-1)-like human syndrome; however, its role in CNS development has not been explored. We show that Spred1 is highly enriched in CNS germinal zones during neurogenesis. Spred1 knockdown increases NSC self-renewal and progenitor proliferation cell-autonomously, and overexpression causes premature differentiation. Surprisingly, Spred1 knockdown in vivo in the embryonic mouse forebrain frequently resulted in periventricular heterotopia, developmental abnormalities often associated with mutations in genes in the vesicular trafficking pathway that cause disruption of germinal zones and impair cell migration. In cortical progenitor cells, Spred1 localizes within distinct vesicles, indicating a potential role in transport. Spred1 knockdown gradually leads to disruption of the apical ventricular zone and loss of radial glia alignment. This impairs late neuronal migration, resulting in the formation of periventricular masses. Thus, Spred1 is critical for normal cortical development, as it modulates progenitor self-renewal/proliferation and helps maintain the integrity and organization of germinal zones.[Keywords: Spred1; neural stem cells; self-renewal; MAPK-ERK signaling; periventricular heterotopia] Supplemental material is available at http://www.genesdev.org.

Glucocorticoid receptors in the retina, Müller glia and the formation of Müller glia-derived progenitors

“…Spred1 and Spred2 are known to be expressed by Müller glia, and levels of Spred1 are influenced by retinal degeneration (Roesch et al, 2008(Roesch et al, , 2012. Interestingly, Spred1 is enriched in neural stem cells in the rodent ventricular zone and acts to suppress proliferation (Phoenix and Temple, 2010). Collectively, our data suggest that activation of GCR may upregulate transcription of Spred1 to dampen MAPK signaling in Müller glia in damaged retinas, but not in FGF2-treated retinas in the absence of damage.…”

Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype–phenotype correlation

“…10,11 Similarly to neurofibromin, SPRED1 is a negative regulator of RAS-MAPK signaling. 12 Before the cloning of the NF1 gene two other related disorders, Watson syndrome (WS) and NF1-Noonan syndrome (NFNS), had been described clinically, both have been shown to be caused by NF1 mutations. Watson 13 described autosomal dominant inheritance of PS, multiple CALS spots and intelligence at the lower end of the normal range.…”

Identification of SPRED2 (Sprouty-related Protein with EVH1 Domain 2) as a Negative Regulator of the Hypothalamic-Pituitary-Adrenal Axis

“…In addition, SPRED1 knockdown studies in mice underlined its importance for brain development and supported the hypothesis of its involvement in vesicle transport (26,37).…”

“…SPRED1 has been shown to be expressed predominantly in the brain (21,26) and to be enriched in the central nervous system, where it mediates cortical development, neural stem cell proliferation, and vesicular trafficking (26,37). Recently, it has been shown that germ line loss-of-function mutations of SPRED1 cause the neurofibromatosis type 1-like Legius syndrome, associated with café-au-lait spots, facial abnormalities, and behavioral and learning problems (31,(33)(34)(35).…”