TY - JOUR
T1 - A conditional null allele of Dync1h1 enables targeted analyses of dynein roles in neuronal length sensing
AU - Di Pizio, Agostina
AU - Marvaldi, Letizia
AU - Birling, Marie-Christine
AU - Okladnikov, Nataliya
AU - Dupuis, Luc
AU - Fainzilber, Mike
AU - Rishal, Ida
N1 - This work was funded by Agence Nationale de la Recherche, France (ANR-10-JCJC-1101 to L.D.), the Motor Neuron Disease Association (Dupuis/Apr16/852-791 to L.D.), and the Israel Science Foundation (ISF 1337/18 to M.F. and I.R.). M.F. is the incumbent of the Chaya Professorial Chair in Molecular Neuroscience at the Weizmann Institute of Science. Open access funding provided by the Weizmann Institute of Science. Deposited in PMC for immediate release.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Size homeostasis is a fundamental process in biology and is particularly important for large cells such as neurons. We previously proposed a motor-dependent length-sensing mechanism wherein reductions in microtubule motor levels would be expected to accelerate neuronal growth, and validated this prediction in dynein heavy chain 1 Loa mutant (Dync1h1Loa) sensory neurons. Here, we describe a new mouse model with a conditional deletion allele of exons 24 and 25 in Dync1h1. Homozygous Islet1-Cre-mediated deletion of Dync1h1 (Isl1-Dync1h1−/−), which deletes protein from the motor and sensory neurons, is embryonic lethal, but heterozygous animals (Isl1-Dync1h1+/−) survive to adulthood with ∼50% dynein expression in targeted cells. Isl1-Dync1h1+/− sensory neurons reveal accelerated growth, as previously reported in Dync1h1Loa neurons. Moreover, Isl1-Dync1h1+/− mice show mild impairments in gait, proprioception and tactile sensation, similar to what is seen in Dync1h1Loa mice, confirming that specific aspects of the Loa phenotype are due to reduced dynein levels. Isl1-Dync1h1+/− mice also show delayed recovery from peripheral nerve injury, likely due to reduced injury signal delivery from axonal lesion sites. Thus, conditional deletion of Dync1h1 exons 24 and 25 enables targeted studies of the role of dynein in neuronal growth.
AB - Size homeostasis is a fundamental process in biology and is particularly important for large cells such as neurons. We previously proposed a motor-dependent length-sensing mechanism wherein reductions in microtubule motor levels would be expected to accelerate neuronal growth, and validated this prediction in dynein heavy chain 1 Loa mutant (Dync1h1Loa) sensory neurons. Here, we describe a new mouse model with a conditional deletion allele of exons 24 and 25 in Dync1h1. Homozygous Islet1-Cre-mediated deletion of Dync1h1 (Isl1-Dync1h1−/−), which deletes protein from the motor and sensory neurons, is embryonic lethal, but heterozygous animals (Isl1-Dync1h1+/−) survive to adulthood with ∼50% dynein expression in targeted cells. Isl1-Dync1h1+/− sensory neurons reveal accelerated growth, as previously reported in Dync1h1Loa neurons. Moreover, Isl1-Dync1h1+/− mice show mild impairments in gait, proprioception and tactile sensation, similar to what is seen in Dync1h1Loa mice, confirming that specific aspects of the Loa phenotype are due to reduced dynein levels. Isl1-Dync1h1+/− mice also show delayed recovery from peripheral nerve injury, likely due to reduced injury signal delivery from axonal lesion sites. Thus, conditional deletion of Dync1h1 exons 24 and 25 enables targeted studies of the role of dynein in neuronal growth.
UR - http://www.scopus.com/inward/record.url?scp=85141003685&partnerID=8YFLogxK
U2 - https://doi.org/10.1242/jcs.260220
DO - https://doi.org/10.1242/jcs.260220
M3 - مقالة
SN - 0021-9533
VL - 136
JO - Journal of Cell Science
JF - Journal of Cell Science
IS - 5
M1 - jcs260220
ER -