Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease.
The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington's disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdhd•hyp). We demonstrated that Hdhd•hypmice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdhd•hypembryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
Eduardo E
EE
Arteaga-Bracho
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA; Behavioral Core Facility, Albert Einstein College of Medicine, Bronx, NY, USA.
Maria
M
Gulinello
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
Michael L
ML
Winchester
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
Nandini
N
Pichamoorthy
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
Jenna R
JR
Petronglo
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
Alicia D
AD
Zambrano
The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
Julio
J
Inocencio
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
Chirstopher D
CD
De Jesus
The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
Joseph O
JO
Louie
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA.
Solen
S
Gokhan
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA; Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA; Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Center for Epigenomics, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
Mark F
MF
Mehler
Roslyn and Leslie Goldstein Laboratory for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Brain Disorders and Neural Regeneration, Albert Einstein College of Medicine, Bronx, NY, USA; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: aldrin.molero@einstein.yu.edu.
Aldrin E
AE
Molero
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D000071058:Huntingtin Protein / Q000172:deficiency* / Q000235:genetics; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000150:complications / Q000209:etiology*; D011596:Psychomotor Disorders / Q000209:etiology / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D066127:White Matter / Q000473:pathology
D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
Degeneration; Development; Gliogenesis; Huntingtin; Huntington's disease; Loss-of-function; Maturation; Myelin; Neurogenesis; Pathogenesis