Biomedical subjects

Ignacio Moreno de Alborán

Publications and source records attributed to Ignacio Moreno de Alborán.

5 recordsLinked to original sources

PubMed2006

N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth.

We examined the genetic requirements for the Myc family of oncogenes in normal Sonic hedgehog (Shh)-mediated cerebellar granule neuronal precursor (GNP) expansion and in Shh pathway-induced medulloblastoma formation. In GNP-enriched cultures derived from N-myc(Fl/Fl) and c-myc(Fl/Fl) mice, disruption of N-myc, but not c-myc, inhibited the proliferative response to Shh. Conditional deletion of c-myc revealed that, although it is necessary for the general regulation of brain growth, it is less important for cerebellar development and GNP expansion than N-myc. In vivo analysis of compound mutants carrying the conditional N-myc null and the activated Smoothened (ND2:SmoA1) alleles showed, that although granule cells expressing the ND2:SmoA1 transgene are present in the N-myc null cerebellum, no hyperproliferation or tumor formation was detected. Taken together, these findings provide in vivo evidence that N-myc acts downstream of Shh/Smo signaling during GNP proliferation and that N-myc is required for medulloblastoma genesis even in the presence of constitutively active signaling from the Shh pathway.

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PubMed2006

Hypertrophic growth in cardiac myocytes is mediated by Myc through a Cyclin D2-dependent pathway.

c-Myc (Myc) is highly expressed in developing embryos where it regulates body size by controlling proliferation but not cell size. However, Myc is also induced in many postmitotic tissues, including adult myocardium, in response to stress where the predominant form of growth is an increase in cell size (hypertrophy) and not number. The function of Myc induction in this setting is unproven. Therefore, to explore Myc's role in hypertrophic growth, we created mice where Myc can be inducibly inactivated, specifically in adult myocardium. Myc-deficient hearts demonstrated attenuated stress-induced hypertrophic growth, secondary to a reduction in cell growth of individual myocytes. To explore the dependence of Myc-induced cell growth on CycD2, we created bigenic mice where Myc can be selectively activated in CycD2-null adult myocardium. Myc-dependent hypertrophic growth and cell cycle reentry is blocked in CycD2-deficient hearts. However, in contrast to Myc-induced DNA synthesis, hypertrophic growth is independent of CycD2-induced Cdk2 activity. These data suggest that Myc is required for a normal hypertrophic response and that its growth-promoting effects are also mediated through a CycD2-dependent pathway.

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PubMed2005

c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver.

The c-Myc protein is a transcription factor implicated in the regulation of multiple biological processes, including cell proliferation, cell growth, and apoptosis. In vivo overexpression of c-myc is linked to tumor development in a number of mouse models. Here, we show that perinatal inactivation of c-Myc in liver causes disorganized organ architecture, decreased hepatocyte size, and cell ploidy. Furthermore, c-Myc appears to have distinct roles in proliferation in liver. Thus, postnatal hepatocyte proliferation does not require c-Myc, whereas it is necessary for liver regeneration in adult mice. These results show novel physiological functions of c-myc in liver development and hepatocyte proliferation and growth.

Animals↗

PubMed2005

Endogenous Myc controls mammalian epidermal cell size, hyperproliferation, endoreplication and stem cell amplification.

The transcription factor Myc (c-Myc) plays an important role in cell growth and cell death, yet its physiological function remains unclear. Ectopic activation of Myc has been recently suggested to regulate cell mass, and Drosophila dmyc controls cellular growth and size independently of cell division. By contrast, it has been proposed that in mammals Myc controls cell division and cell number. To gain insights into this debate we have specifically knocked out Myc in epidermis. Myc epidermal knockout mice are viable and their keratinocytes continue to cycle, but they display severe skin defects. The skin is tight and fragile, tears off in areas of mechanical friction and displays impaired wound healing. Steady-state epidermis is thinner, with loss of the proliferative compartment and premature differentiation. Remarkably, keratinocyte cell size, growth and endoreplication are reduced, and stem cell amplification is compromised. The results provide new and direct evidence for a role for endogenous Myc in cellular growth that is required for hyperproliferative cycles and tissue homeostasis.

Animals↗

PubMed2003

Cell death during lymphocyte development and activation.

The development and homeostasis of the immune system requires an exquisite balance between cell proliferation and cell death. In this review, we discuss several in vivo and in vitro models that have been developed to help understand the importance of apoptosis during B and T cell development and activation.

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