Use of progenitors in the treatment of human disease will rely on the ability to direct their differentiation and integration into the surrounding tissue. Understanding the molecular mechanisms that guide progenitor fate will be crucial toward achieving this goal. We have taken the approach of identifying and understanding genes that cause human disorders of progenitor development. Mutations in filamin A (FLNA) lead to the brain malformation, periventricular heterotopia (PH). Mutations in the filamin B (FLNB) gene result in skeletal chondrodysplasias (SC). The human phenotypes associated with these disorders suggest that filamin proteins are important in progenitor development. During cortical development, neural progenitors undergo rapid proliferation and cell fate decisions in the ventricular/subventricular zones (VZ/SVZ) along the brain neuroependyma. PH results in a thinned cortex and nodules of neurons along the neuroependyma suggesting a neural stem cell defect. Similarly, skeletal development begins with expansion of chondrocyte condensations within the proliferative zones, leading to a gradual increase in bone length. SC due to FLNB mutations leads to a progressive shortening of bones, and delayed and ectopic ossification, also indicating a bone precursor defect. Overall, this project seeks to understand how filamin and formin function dictates stem cell expansion and differentiation. The potential impact of this work is to gain a better understanding of the role of filamins and formins in neural and chondrocyte stem cell physiology. Since many of the goals of stem cell biology are related to their potential use as therapeutic agents, our work will help to determine the role of filamins and formins in maintaining or differentiating these cells, so that these stem cells can be made to perform the functions that will be required of them in patients.
Ferland RJ, Batiz LF, Neal J, Lian G, Bundock E, Lu J, Hsiao YC, Diamond R, Mei D, Banham AH, Brown PJ, Vanderburg CR, Joseph J, Hecht JL, Folkerth R, Guerrini R, Walsh CA, Rodriguez EM, Sheen VL. Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia. Hum Mol Genet. 2009 Feb 1;18(3):497-516.
Papandrea D, Anderson TM, Herron BJ, Ferland RJ. Dissociation of seizure traits in inbred strains of mice using the flurothyl kindling model of epileptogenesis. Exp Neurol. 2009 Jan;215(1):60-8.
Doering JE, Kane K, Hsiao YC, Yao C, Shi B, Slowik AD, Dhagat B, Scott DD, Ault JG, Page-McCaw PS, Ferland RJ. Species differences in the expression of Ahi1, a protein implicated in the neurodevelopmental disorder Joubert syndrome, with preferential accumulation to stigmoid bodies. J Comp Neurol. 2008 Nov 10;511(2):238-56.
Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008 Jul 11;321(5886):218-23.
Yu F, Hill RS, Schaffner SF, Sabeti PC, Wang ET, Mignault AA, Ferland RJ, Moyzis RK, Walsh CA, Reich D. Comment on "Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens". Science. 2007 Apr 20;316(5823):370.
Ferland RJ, Gaitanis JN, Apse K, Tantravahi U, Walsh CA, Sheen VL. Periventricular nodular heterotopia and Williams syndrome. Am J Med Genet A. 2006 Jun 15;140(12):1305-11.
Sheen VL, Ferland RJ, Harney M, Hill RS, Neal J, Banham AH, Brown P, Chenn A, Corbo J, Hecht J, Folkerth R, Walsh CA. Impaired proliferation and migration in human Miller-Dieker neural precursors. Ann Neurol. 2006 Jul;60(1):137-44.
Sheen VL, Ferland RJ, Neal J, Harney M, Hill RS, Banham A, Brown P, Chenn A, Corbo J, Hecht J, Folkerth R, Walsh CA. Neocortical neuronal arrangement in Miller Dieker syndrome. Acta Neuropathol. 2006 May;111(5):489-96.
Basel-Vanagaite L, Attia R, Yahav M, Ferland RJ, Anteki L, Walsh CA, Olender T, Straussberg R, Magal N, Taub E, Drasinover V, Alkelai A, Bercovich D, Rechavi G, Simon AJ, Shohat M. The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet. 2006 Mar;43(3):203-10.
Ferland RJ, Li X, Buhlmann JE, Bu X, Walsh CA, Lim B. Characterization of Rho-GDIgamma and Rho-GDIalpha mRNA in the developing and mature brain with an analysis of mice with targeted deletions of Rho-GDIgamma. Brain Res. 2005 Aug 23;1054(1):9-21.
Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet. 2004 Sep;36(9):1008-13.