Lot1 is a key element of the pituitary adenylate cyclase-activating polypeptide (PACAP)/cyclic AMP pathway that negatively regulates neuronal precursor proliferation
Authors: Tatiana Fila
Christophe Crochemore
Stefania Trazzi
Elisabetta Ciani
Renata Bartesaghi
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: tumor suppressor gene; Lot1; brain development; cerebellar development; granule cells
Affiliations: Department of Human and General Physiology, University of Bologna, Piazza di Porta San Donato 2, Bologna, Italy.

Abstract:  The tumor suppressor gene Lot1 is highly expressed during brain development. During cerebellar development, Lot1 is expressed by proliferating granule cells with a time course matching the expression of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor, a neuropeptide receptor that plays an important role in the regulation of granule cell proliferation/survival. Although it has become clear that Lot1 is a negative regulator of cell division in tumor cells, its role in neuronal proliferation is not understood. We previously demonstrated that in cerebellar granule cells Lot1 expression is regulated by the PACAP/cAMP system. The aim of this study was to investigate the role played by Lot1 in neuron proliferation/survival and to identify the molecular mechanisms underlying its actions. Using a Lot1-inducible expression system, we found that in PC12 cells Lot1 negatively regulates proliferation and favors differentiation by up-regulating the expression of the PACAP receptor. In cerebellar granule cells in culture, an increase in Lot1 expression was paralleled by inhibition of proliferation and up-regulation of the PACAP receptor, which in turn positively regulated Lot1 expression. Silencing of Lot1 leads to an increase in granule cell proliferation and a reduction in survival. Confirming the in vitro results, in vivo experiments showed that PACAP induced an increase in Lot1 expression that was paralleled by inhibition of cerebellar granule cell proliferation. These data show that Lot1 is a key element of the PACAP/cAMP pathway that negatively regulates neuronal precursor proliferation. The existence of a PACAP receptor/Lot1-positive feedback loop may powerfully regulate neural proliferation during critical phases of cerebellar development. 

Retracted: No

PubPeer comments:
 Figure 3F. https: imgur.com aFApa2S , 
 2020 correction. https: www.jbc.org content 295 11 3746.short In Fig. 3F, the image corresponding to the u03b2-tubulin III was composed of spliced lanes. An image obtained from an immunoblot where the samples were loaded consecutively is now shown in Fig. 3F. This correction does not affect the results or the conclusions of this work. , 
 Dear Dr. Ciani and collaborators, in your publication, the control image in Fig. 5C is identical to the control image in Fig. 6G. These experiments are described as independent in the text, therefore the reuse of control images appears not in line with scientific standards. I would be grateful if you could clarify this issue. Best, ![file] , 
 The original figure includes only one lane (4 samples) and the corrected one includes two lanes (8 samples), and the blots look completely different. Additionally, panel G only includes one lane. I am surprised that the journal allowed this change without changing the relevant densitometry graph where n is not specified and similarly did not provide the corrected image for panel G.![file] ,