Cellular and Molecular Neurobiology

, Volume 38, Issue 4, pp 841–859 | Cite as

Expression of Gas1 in Mouse Brain: Release and Role in Neuronal Differentiation

  • Elizabeth Bautista
  • Natanael Zarco
  • Nicolás Aguirre-Pineda
  • Manuel Lara-Lozano
  • Paula Vergara
  • Juan Antonio González-Barrios
  • Raúl Aguilar-Roblero
  • José Segovia
Original Research


Growth arrest-specific 1 (Gas1) is a pleiotropic protein that induces apoptosis of tumor cells and has important roles during development. Recently, the presence of two forms of Gas1 was reported: one attached to the cell membrane by a GPI anchor; and a soluble extracellular form shed by cells. Previously, we showed that Gas1 is expressed in different areas of the adult mouse CNS. Here, we report the levels of Gas1 mRNA protein in different regions and analyzed its expressions in glutamatergic, GABAergic, and dopaminergic neurons. We found that Gas1 is expressed in GABAergic and glutamatergic neurons in the Purkinje-molecular layer of the cerebellum, hippocampus, thalamus, and fastigial nucleus, as well as in dopaminergic neurons of the substantia nigra. In all cases, Gas1 was found in the cell bodies, but not in the neuropil. The Purkinje and the molecular layers show the highest levels of Gas1, whereas the granule cell layer has low levels. Moreover, we detected the expression and release of Gas1 from primary cultures of Purkinje cells and from hippocampal neurons as well as from neuronal cell lines, but not from cerebellar granular cells. In addition, using SH-SY5Y cells differentiated with retinoic acid as a neuronal model, we found that extracellular Gas1 promotes neurite outgrowth, increases the levels of tyrosine hydroxylase, and stimulates the inhibition of GSK3β. These findings demonstrate that Gas1 is expressed and released by neurons and promotes differentiation, suggesting an important role for Gas1 in cellular signaling in the CNS.


Growth arrest-specific 1 (Gas1) Glycogen synthase kinase 3β (GSK3β) Hippocampus Vesicular glutamate transporter 2 (VGLUT2) Glutamic acid decarboxylase of 67 kDa (GAD67Retinoic acid (RA) 



This study was partially supported by CONACyT (Mexico) Grants 239516 (JS) and PAPIIT/DGAPA IN205917 (R.A.-R.). The authors wish to thank Araceli Navarrete Alonso for their technical support and Rubén Sánchez for his laboratory assistance.

Author Contributions

Designed research: EB, NZ, MLL, and JS; performed research: EB, MLL, NZ, NA-P, and PV; analyzed data: JAGB, EB, RAR, and JS; wrote the manuscript: EB and JS.

Compliance with Ethical Standards

Conflict of interest

The authors declare no competing financial interests nor other potential conflicts of interest.

Ethical Approval

Experiments were performed according to the current Mexican legislation NOM-062-ZOO-1999 (SAGARPA) and internal institutional guidelines, per authorization 0152-03, from Cinvestav (Comité Interno para el Cuidado y Uso de Animales de Laboratorio).

Supplementary material

10571_2017_559_MOESM1_ESM.tif (238 kb)
Supplementary Fig. 1 Gas1 is expressed in the (AC) cerebellar cortex (DF) medulla oblongata and (GI) cortex of the adult mouse brain. Bar: (A and D) 100 μm. (TIFF 237 kb)
10571_2017_559_MOESM2_ESM.tif (23 kb)
Supplementary Fig. 2 Levels of gas1 mRNA from different brain regions, as determined by RT-PCR. B (-) no cDNA added; NP, proliferating NIH/3T3 cells; N24, arrested NIH/3T3 cells; Cb, cerebellum; Hip, hippocampus; Tal, Thalamus (TIFF 23 kb)
10571_2017_559_MOESM3_ESM.tif (211 kb)
Supplementary Fig. 3 Gas1 co-localizes with GAD67 and VGLUT2 in hippocampus CA1. (A-B) Gas1 (green) is present in the soma of GABAergic neurons (GAD67 +: red) of the stratum oriens and (D-E) in the soma of glutamatergic neurons (VGLUT2+: red) of hippocampal CA1 pyramidal cells. Nuclei were counterstained with DAPI (blue). Cells indicated by arrows in A and D, are amplified in B and D, respectively. Bar: (A and D) 100 μm, (B and E) 10 μm. C and F represent the areas examined. Abbreviations are expounded in Table 1 (TIFF 211 kb)
10571_2017_559_MOESM4_ESM.tif (246 kb)
Supplementary Fig. 4 Gas1 is expressed in GABAergic and glutamatergic neurons of hippocampus CA2. (A-B) Gas1 (green) is present in the soma of GABAergic neurons (GAD67 +: red) of stratum oriens and (D-E) in the soma of glutamatergic neurons (VGLUT2+: red) of hippocampal CA2 pyramidal cells. Nuclei were counterstained with DAPI (blue). Cells indicated by arrows in A and D, are amplified in B and E, respectively. Bar: (A and D) 100 μm, (B and E) 10 μm. C and F show the areas examined. Abbreviations are expound in Table 1 (TIFF 245 kb)
10571_2017_559_MOESM5_ESM.tif (246 kb)
Supplementary Fig. 5 Gas1 is expressed in GABAergic neurons of the molecular layer of the hippocampus. (A-B) Gas1 (green) is present in the soma of GABAergic neurons (GAD67 +: red) of the molecular layer but not (D-E) in the GABAergic neuropil of the CA2 pyramidal layer. Nuclei were counterstained with DAPI (blue). Cell indicated by arrow in A is amplified in B; the inset in B is amplified in E. Bar: (A and D) 100 μm, (B and E) 10 μm. C and F show the areas examined. Abbreviations are expounded in Table 1 (TIFF 245 kb)
10571_2017_559_MOESM6_ESM.tif (39 kb)
Supplementary Fig. 6 Effect of Gas1 on cell viability. SH-SY5Y cells were cultured for 7 days in the presence of AR with different concentration of rh_Gas1. Mitochondrial activity was determined by the MTT assay and is expressed as percentage of viable cells. We used one-way ANOVA followed by Tukey´s post hoc multiple comparison test. Bars are mean ± SEM (n = 3). There were no significant differences among groups (TIFF 39 kb)


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Elizabeth Bautista
    • 1
  • Natanael Zarco
    • 1
  • Nicolás Aguirre-Pineda
    • 1
  • Manuel Lara-Lozano
    • 1
    • 2
  • Paula Vergara
    • 1
  • Juan Antonio González-Barrios
    • 2
  • Raúl Aguilar-Roblero
    • 3
  • José Segovia
    • 1
  1. 1.Departamento de Fisiología, Biofísica y NeurocienciasCentro de Investigación y de Estudios Avanzados del IPNMexicoMexico
  2. 2.Laboratorio de Medicina Genómica, Hospital Regional 1 de OctubreInstituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE)MexicoMexico
  3. 3.Departamento de Neurociencia Cognitiva, Instituto de Fisiología CelularUniversidad Nacional Autónoma de MéxicoMexicoMexico

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