Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

AbstractPatients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and are diagnosed by the hindbrain “molar tooth sign” malformation. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles, which create a deepened interpeduncular fossa. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation and axon guidance through vertebrate Hedgehog signaling. In patients, point mutations in ARL13B cause Joubert syndrome. In order to understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. Additionally, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally, showed normal tract targeting and vermis size. Taken together, our data indicate that ARL13B is critical for superior cerebellar peduncle targeting, likely via Hedgehog signaling, as well as control of cerebellar vermis size. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.Summary statementJoubert syndrome is diagnosed by the hindbrain “molar tooth sign” malformation. Using mouse models, we show loss of the ciliary GTPase ARL13B, mutations in which lead to Joubert syndrome, result in two features of the molar tooth sign: hypoplasia of the cerebellar vermis and inappropriate targeting of the superior cerebellar peduncles. Furthermore, we demonstrate that loss of vertebrate Hedgehog signaling may be the underlying disrupted mechanism as we extend its role in axon guidance to the superior cerebellar peduncles.

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Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Genetics ◽

10.1093/genetics/iyab084 ◽

2021 ◽

Author(s):

Sarah K Suciu ◽

Alyssa B Long ◽

Tamara Caspary

Keyword(s):

Axon Guidance ◽

Cell Fate ◽

Hedgehog Signaling ◽

Joubert Syndrome ◽

Molar Tooth ◽

Cerebellar Vermis ◽

Superior Cerebellar Peduncle ◽

Molar Tooth Sign ◽

Radiological Abnormality ◽

Cerebellar Peduncle

Abstract Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and a hindbrain malformation described as the “molar tooth sign” due to its appearance on an MRI. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation and axon guidance through vertebrate Hedgehog signaling. In patients, mutations in ARL13B cause Joubert syndrome. In order to understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. Additionally, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally, showed normal tract targeting and vermis width. Taken together, our data indicate that ARL13B is critical for control of cerebellar vermis width as well as superior cerebellar peduncle axon guidance, likely via Hedgehog signaling. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.

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Periventricular nodular heterotopias an atypical manifestation of Joubert syndrome

Nepal Journal of Neuroscience ◽

10.3126/njn.v18i1.33295 ◽

2021 ◽

Vol 18 (1) ◽

pp. 73-76

Author(s):

Himanshu Mishra ◽

Amit Kumar

Keyword(s):

Fourth Ventricle ◽

Joubert Syndrome ◽

Molar Tooth ◽

Cortical Atrophy ◽

Superior Cerebellar Peduncle ◽

Periventricular Nodular Heterotopia ◽

Molar Tooth Sign ◽

Nodular Heterotopia ◽

Cerebellar Peduncle ◽

Echogenic Kidneys

Joubert syndrome (JS) is characterized by varying degrees of mid and hindbrain malformations. A thickened superior cerebellar peduncle (“molar tooth sign”), varying degree of cerebellar vermian clefting, and an oddly shaped (“bat-wing”) fourth ventricle are essential diagnostic cues on imaging. When JS is associated with renal, ocular, hepatobiliary, or oro-facial abnormalities, the term Joubert syndrome and related disorders (JSRD) is used. We report a classic case of this rare disease in a 5 month old male child who presented to our department for assessment of developmental delay. MRI revealed molar-tooth appearance of midbrain, an abnormally shaped fourth ventricle, and vermian aplasia. Additional findings present in our case were corpus callosum dysgenesis, colpocephaly, generalized cortical atrophy, and periventricular nodular heterotopia. Subsequently, an ultrasound of the abdomen was performed to look for any associated anomalies. It revealed diffuse bilateral echogenic kidneys with attenuated corticomedullary differentiation (likely due to micro cysts in medulla) and few thin-walled peripheral renal cortical cysts. Callosal dysgenesis, colpocephaly, cortical atrophy and cortical heterotopias are less common manifestations of JS/JSRD and periventricular nodular heterotopia has been infrequently reported in cases of Joubert syndrome. Key-words: Joubert Syndrome, MRI, Molar Tooth Sign, Periventricular Nodular Heterotopia, Bilateral Echogenic Kidneys

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Another Piece of the Puzzle of Anomalous Connectivity in Joubert's Syndrome

Neuropediatrics ◽

10.1055/s-0041-1732310 ◽

2021 ◽

Author(s):

Avner Meoded ◽

Marcia Kukreja ◽

Gunes Orman ◽

Eugen Boltshauser ◽

Thierry A.G.M. Huisman

Keyword(s):

White Matter ◽

Diffusion Tensor ◽

Three Dimensional ◽

Axonal Guidance ◽

Molar Tooth ◽

Superior Cerebellar Peduncle ◽

Corticospinal Tracts ◽

Cerebellar Peduncles ◽

Cerebellar Peduncle ◽

Magnetic Resonance Imaging Mri

AbstractWe report on the conventional and diffusion tensor imaging (DTI) findings of a 2-year-old child with clinical presentation of Joubert's Syndrome (JS) and brainstem structural abnormalities as depicted by neuroimaging.Conventional magnetic resonance imaging (MRI) showed a “molar tooth” configuration of the brainstem. A band-like formation coursing in an apparent axial plane anterior to the interpeduncular fossa was noted and appeared to partially cover the interpeduncular fossa.DTI maps and three-dimensional (3D) tractography demonstrated a prominent red-encoded white matter bundle anterior to the midbrain. Probable aberrant course of the bilateral corticospinal tracts (CST) was also depicted. Absence of the decussation of the superior cerebellar peduncles and elongated thickened, horizontal superior cerebellar peduncle (SCP) reflecting the molar tooth sign were also shown.Our report and the review of the published cases suggest that DTI and tractography may be very helpful to differentiate between interpeduncular heterotopias and similarly located white matter bundles corroborating the underlying etiology of axonal guidance disorders in the complex group of ciliopathies including JS. Our case represents an important additional puzzle piece to explore the variability of these ciliopathies.

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White matter differences between essential tremor and Parkinson disease

Neurology ◽

10.1212/wnl.0000000000006694 ◽

2018 ◽

Vol 92 (1) ◽

pp. e30-e39 ◽

Cited By ~ 5

Author(s):

Meher R. Juttukonda ◽

Giulia Franco ◽

Dario J. Englot ◽

Ya-Chen Lin ◽

Kalen J. Petersen ◽

...

Keyword(s):

White Matter ◽

Parkinson Disease ◽

Essential Tremor ◽

Fractional Anisotropy ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Superior Cerebellar Peduncle ◽

Radial Diffusivity ◽

Cerebellar Peduncles ◽

Cerebellar Peduncle

ObjectiveTo assess white matter integrity in patients with essential tremor (ET) and Parkinson disease (PD) with moderate to severe motor impairment.MethodsSedated participants with ET (n = 57) or PD (n = 99) underwent diffusion tensor imaging (DTI) and fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values were computed. White matter tracts were defined using 3 well-described atlases. To determine candidate white matter regions that differ between ET and PD groups, a bootstrapping analysis was applied using the least absolute shrinkage and selection operator. Linear regression was applied to assess magnitude and direction of differences in DTI metrics between ET and PD populations in the candidate regions.ResultsFractional anisotropy values that differentiate ET from PD localize primarily to thalamic and visual-related pathways, while diffusivity differences localized to the cerebellar peduncles. Patients with ET exhibited lower fractional anisotropy values than patients with PD in the lateral geniculate body (p < 0.01), sagittal stratum (p = 0.01), forceps major (p = 0.02), pontine crossing tract (p = 0.03), and retrolenticular internal capsule (p = 0.04). Patients with ET exhibited greater radial diffusivity values than patients with PD in the superior cerebellar peduncle (p < 0.01), middle cerebellar peduncle (p = 0.05), and inferior cerebellar peduncle (p = 0.05).ConclusionsRegionally, distinctive white matter microstructural values in patients with ET localize to the cerebellar peduncles and thalamo-cortical visual pathways. These findings complement recent functional imaging studies in ET but also extend our understanding of putative physiologic features that account for distinctions between ET and PD.

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