Elsevier

Developmental Biology

Volume 448, Issue 1, 1 April 2019, Pages 36-47
Developmental Biology

Loss of the neurodevelopmental Joubert syndrome causing protein, Ahi1, causes motor and muscle development delays independent of central nervous system involvement

https://doi.org/10.1016/j.ydbio.2019.01.014Get rights and content
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Highlights

  • Mice with targeted deletions of Ahi1 show deficits in motor behavior.

  • Primary myoblasts from Ahi1 knockout mice fail to properly differentiate in vitro.

  • Muscle in Ahi1-/- mice show reduced myonuclear domain&fiber cross sectional area.

  • Reductions in the muscle filament, desmin, are present in embryonic Ahi1-/- mice.

  • No neuroanatomical malformations are observed in FVB/NJ Ahi1-/- mice.

Abstract

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.

Abbreviations

AHI1
Abelson helper integration site 1
BrdU
5-bromo-2′-deoxyuridine
CNS
Central nervous system
CSA
Cross sectional area
DM
Differentiation medium
DSHB
Developmental studies hybridoma bank
MHC
Myosin heavy chain
JBTS
Joubert syndrome
PM
Proliferation medium
RF
Rectus femoris
SCP
Superior cerebellar peduncles
VI
Vastus intermedius

Keywords

Joubert syndrome
Ahi1
Hypotonia
Myogenic
Desmin

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