The Neuropathophysiology Unit is interested in the genetic regulation of neural development and in the cellular and molecular basis of neurodevelopmental disorders, primarily congenital cerebellar ataxias. For many years, we have used the cerebellum as a model system, and have studied its development using neural cell lines, neural stem cells, primary neural progenitors, organotypic tissue sections, and genetically engineered mouse lines, several of which developed by us.
We are interested in the genetic regulation of neural development and in the cellular and molecular basis of neurodevelopmental disorders, primarily congenital cerebellar ataxias and autism spectrum disorders. We study cerebellar development using cell lines, neural stem cells, primary neural progenitors, organotypic tissue sections, and genetically engineered mouse lines, several of which developed in house. We have been characterizing a murine model of Joubert syndrome (JS), a multisystem disorder featuring cerebellar malformation and dysfunction, besides other neural and extraneural defects. While JS is regarded as a ciliopathy, recent evidence indicates that this disorder may be also due to a dysfunction of the DNA damage repair machinery. We are studying one of the genes mutated in this disease (Zfp423 / ZNF423) and its role, both in DNA repair and in various other aspects of cerebellar development, focusing on the defects observed in JS.
Axonal biology in ALS
Our group has also undertaken a study of axonal biology in murine models of a deadly degenerative disorder of upper and lower motor neurons known as amyotrophic lateral sclerosis (ALS). The repertoire of treatments available to delay disease progression in ALS is severely limited, mostly due to our sketchy understanding of the underlying cellular defects. ALS affects axons and presynaptic terminals belonging to long range fiber tracts, namely the corticobulbar/corticospinal tract and the motor component of peripheral nerves. ALS genes, such as TARDPB, may contribute to axonal RNA metabolism and their mutation may impair splicing and subcellular mRNA localization/maturation, affecting mRNA translation and promoting ribosome frameshifts or nonsense mediated mRNA decay. Since TDP43 directly or indirectly appears to regulate translation, assessing any dysregulation in this process is a highly relevant, yet understudied, topic in ALS research.
Casoni F, Croci L, Bosone C, D'Ambrosio R, Badaloni A, Gaudesi D, Barili V, Sarna JR, Tessarollo L, Cremona O, Hawkes R, Warming S, Consalez GG. Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors. Development 2017 Oct 15;144(20):3686-3697.
Miquelajauregui A, Kribakaran S., Mostany R, Badaloni A, Consalez GG and Portera-Cailliau C. Layer 4 pyramidal neurons exhibit robust dendritic spine plasticity in vivo after input deprivation. J Neurosci 2015 35, 7287-7294.
Espinosa-Medina I, Outin E, Picard CA, Chettouh Z, Dymecki S, Consalez GG, Coppola E, Brunet JF. Neurodevelopment. Parasympathetic ganglia derive from Schwann cell precursors. Science 2014 Jul 4;345(6192):87-90.
Florio M, Leto K, Muzio L, Tinterri A, Badaloni A, Croci L, Zordan P, Barili V, Albieri I, Guillemot F, Rossi F, Consalez GG. Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development. Development 2012 Jul;139(13):2308-20.
Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez GG, Gnecchi-Rusconi T, Montano N, Rabello Casali K, Micheloni S, Barbuti A et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Nat'l Acad Sci USA 2011, 108, 1705-1710.
Masserdotti G, Badaloni A, Green YS, Croci L, Barili V, Bergamini G, Vetter ML, Consalez GG. ZFP423 coordinates Notch and bone morphogenetic protein signaling, selectively up-regulating Hes5 gene expression. J Biol Chem. 2010 Oct 1;285(40):30814-24.
Kieslinger M, Hiechiger S, Dobreva G, Consalez G and Grosschedl R. Early B cell factor 2 regulates hematopoietic stem cell homeostasis in a cell-nonautonomous manner. Cell Stem Cell 2007, 7, 496-507.
Croci L, Chung SH, Masserdotti G, Gianola S, Bizzoca A, Gennarini G, Corradi A, Rossi F, Hawkes R, Consalez GG. A key role for the HLH transcription factor EBF2COE2,O/E-3 in Purkinje neuron migration and cerebellar cortical topography. Development 2006 Jul;133(14):2719-29.
Kieslinger M, Folberth S, Dobreva G, Dorn T, Croci L, Erben R, Consalez GG, Grosschedl R. EBF2 regulates osteoblast-dependent differentiation of osteoclasts. Dev Cell. 2005 Dec;9(6):757-67.
Corradi A, Croci L, Broccoli V, Zecchini S, Previtali S, Wurst W, Amadio S, Maggi R, Quattrini A, Consalez GG. Hypogonadotropic hypogonadism and peripheral neuropathy in Ebf2-null mice. Development 2003 Jan;130(2):401-10.