The research of Carlos Ibáñez utilizes a range of molecular, cellular and genetic techniques to elucidate the functions and molecular mechanisms of action of growth factors and their receptors as a framework from which to approach a wider range of problems, including unresolved issues in structural biology, cell signaling, neural development and, more recently, metabolic regulation. Due to pervasive roles of neuronal growth factors in all aspects of nervous system development, function and repair, this approach has allowed Ibáñez and his colleagues to address a range of fundamental problems in neurobiology, including neurogenesis, neuronal differentiation and survival, axon guidance, synaptogenesis and connectivity. Together with his team, he has pioneered studies on structure-function relationships in neurotrophins, GDNF ligands and receptors, and identified determinants of ligand-receptor interaction and downstream signaling. This work has yielded molecules with novel pharmacological profiles, some of which are being tested in models of human disease. They have identified new ligands, receptors and interactions. They have discovered novel cellular functions, including a new mechanism of cell-cell interaction based on ligand-induced cell adhesion, and new mechanisms of cross-talk between signaling pathways, such as TGF- and Notch. Carlos Ibáñez has more recently become interested in metabolic regulation, primarily through his work on the ALK7 receptor. He discovered ALK7 in 1996, reported the first identification of a ligand in 2001, and a mouse knock-out in 2004. In work performed during the past years, he has discovered an important role for this receptor as a novel regulator of insulin release, fat accumulation and diet-induced obesity. Regular collaborations with the industrial sector have resulted in several patents, some of which underlie the current development of novel therapies for peripheral neuropathies, CNS and metabolic diseases.

Lee ES, Guo T, Srivastava RK, Shabbir A, Ibáñez CF. Activin receptor ALK4 promotes adipose tissue hyperplasia by suppressing differentiation of adipocyte precursors. J Biol Chem. 2023 Jan;299(1):102716. doi: 10.1016/j.jbc.2022.102716. Epub 2022 Nov 18. PMID: 36403856; PMCID: PMC9758429.

Krapacher FA, Fernández-Suárez D, Andersson A, Carrier-Ruiz A, Ibáñez CF. Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization. EMBO J. 2022 Aug 1;41(15):e110721. doi: 10.15252/embj.2022110721. Epub 2022 Jun 22. PMID: 35730718.

Fernández-Suárez D, Krapacher FA, Pietrajtis K, Andersson A, Kisiswa L, Carrier-Ruiz A, Diana MA, Ibáñez CF. Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function. PLoS Biol. 2021 Nov 8;19(11):e3001350. doi: 10.1371/journal.pbio.3001350. PMID: 34748545; PMCID: PMC8601618.

Yi, C., Goh, K. Y., Wong, L. W., Ramanujan, A., Tanaka, K., Sajikumar, S., & Ibanez, C. F. (2021).
Inactive variants of death receptor p75(NTR) reduce Alzheimer`s neuropathology by interfering
with APP internalization. EMBO J, 40(2), e104450. doi:10.15252/embj.2020104450

Gongrich, C., Krapacher, F. A., Munguba, H., Fernandez-Suarez, D., Andersson, A., Hjerling-Leffler,
J., & Ibanez, C. F. (2020). ALK4 coordinates extracellular and intrinsic signals to regulate development
of cortical somatostatin interneurons. J Cell Biol, 219(1). doi:10.1083/jcb.201905002

Marmol, P., Krapacher, F., & Ibanez, C. F. (2020). Control of brown adipose tissue adaptation to
nutrient stress by the activin receptor ALK7. Elife, 9. doi:10.7554/eLife.54721

Guo, T., Marmol, P., Moliner, A., Bjornholm, M., Zhang, C., Shokat, K. M., & Ibanez, C. F. (2014).
Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity. Elife, 3, e03245.
doi:10.7554/eLife.03245

Vilar, M., Charalampopoulos, I., Kenchappa, R. S., Simi, A., Karaca, E., Reversi, A., . . . Ibanez, C. F.
(2009). Activation of the p75 neurotrophin receptor through conformational rearrangement of
disulphide-linked receptor dimers. Neuron, 62(1), 72-83. doi:10.1016/j.neuron.2009.02.020

Bertolino, P., Holmberg, R., Reissmann, E., Andersson, O., Berggren, P. O., & Ibanez, C. F. (2008).
Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function. Proc Natl Acad
Sci U S A, 105(20), 7246-7251. doi:10.1073/pnas.0801285105

Ledda, F., Paratcha, G., Sandoval-Guzman, T., & Ibanez, C. F. (2007). GDNF and GFRalpha1
promote formation of neuronal synapses by ligand-induced cell adhesion. Nat Neurosci, 10(3),
293-300. doi:10.1038/nn1855

Vilar, M., Murillo-Carretero, M., Mira, H., Magnusson, K., Besset, V., & Ibanez, C. F. (2006). Bex1, a
novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle.
EMBO J, 25(6), 1219-1230. doi:10.1038/sj.emboj.7601017

Pozas, E., & Ibanez, C. F. (2005). GDNF and GFRalpha1 promote differentiation and tangential
migration of cortical GABAergic neurons. Neuron, 45(5), 701-713.
doi:10.1016/j.neuron.2005.01.043

Paratcha, G., Ledda, F., & Ibanez, C. F. (2003). The neural cell adhesion molecule NCAM is an
alternative signaling receptor for GDNF family ligands. Cell, 113(7), 867-879. doi:10.1016/s0092-
8674(03)00435-5

Ledda, F., Paratcha, G., & Ibanez, C. F. (2002). Target-derived GFRalpha1 as an attractive guidance
signal for developing sensory and sympathetic axons via activation of Cdk5. Neuron, 36(3), 387-
401. doi:10.1016/s0896-6273(02)01002-4

The Science Behind Nobel Prizes 08403751

Laboratory Introduction