Congress Abstracts - Society for Developmental Biology

Patients with Joubert Syndrome and related disorders (JSRD) suffer from a wide array of symptoms with variable clinical
presentation, including intellectual disability. While JSRD is a rare, autosomal recessive congenital disorder, causative mutations for
JSRD have been identified in the small GTPase, ARL13B, the inositol phosphatase, INPP5E and 16 additional genes, all of which code
for proteins related to primary cilia – thus, JSRD are members of the class of diseases known as ciliopathies. Primary cilia are
essential for Sonic hedgehog (Shh) signaling, and we previously showed that Arl13b regulates Shh signaling in mouse. Here we
investigate the pathogenesis of JSRD in mouse models using a conditional Arl13b allele and a novel, ENU-induced Inpp5e allele. We
found that Arl13b is critical for the localization of Inpp5e to cilia. We also found that Inpp5e regulates Shh signaling in an
overlapping, yet distinct, manner to Arl13b. Together these data are consistent with Inpp5e acting as a specific Arl13b effector.
Through Arl13b conditional deletion, we observed defects in the migration and placement of postmitotic interneurons in the
developing cerebral cortex. We found several guidance cue receptors known to be important for interneuron migration localize to
interneuronal cilia, but their concentration and dynamics were abnormal in the absence of either Arl13b or Inpp5e. While wild type
Arl13b could rescue Arl13b-deficiency, Arl13b variants identified in Joubert patients or an Arl13b variant that fails to localize to cilia
could not compensate. Taken together our data indicate that defects in cilia-dependent signaling in interneuron development may
contribute to the neurological deficits in JSRD patients.
Program/Abstract # 317
Invasive adhesion polarizes heart progenitor induction
Davidson, Bradley (Swarthmore College, USA); Norton, Jennifer; Cooley, James (University of Arizona, USA); Cota, Christina
(Swarthmore College, USA)
Cell-matrix adhesion strongly influences developmental signaling. Resulting impacts on cell migration and tissue morphogenesis are
well characterized. However, the in vivo impact of adhesion on fate induction remains ambiguous. Here we employ the simple
chordate Ciona intestinalis to delineate an essential, in vivo role for matrix adhesion in heart progenitor induction. In Ciona precardiac
founder cells, invasion of the underlying epidermis promotes localized induction of the heart progenitor lineage. We found that
these epidermal invasions are associated with matrix adhesion along the pre-cardiac cell/epidermal boundary. Through targeted
manipulations of RAP GTPase activity, we were able to manipulate pre-cardiac cell-matrix adhesion. Targeted disruption of precardiac
cell-matrix adhesion blocked heart progenitor induction. Conversely, increased matrix adhesion generated expanded induction.
We were also able to selectively restore cell-matrix adhesion and heart progenitor induction through targeted expression of either Ci-
Integrin Beta 2 or its predicted partner Ci-Integrin Alpha 2. These results indicate that matrix adhesion functions as a necessary and
sufficient extrinsic cue for regional heart progenitor induction. Additionally, tandem manipulations indicate that adhesion and invasion
regionalize signaling through synergistic, cross-regulatory interactions. Thus, it appears that reciprocal adhesive/protrusive circuitry
associated with directed migration has been co-opted to generate robust, regional induction. Furthermore, time-lapse imaging indicates
that cytokinesis acts as an intrinsic regulator of heart progenitor specification by facilitating localized maturation of adhesive foci.
These findings have profound implications for vertebrate heart development and stem cell biology.
Program/Abstract # 318
Dynamic membranes mediate heart progenitor induction in Ciona.
Cota, Christina (Swarthmore College, USA)
Integrin receptors play an essential role in matrix adhesion during morphogenesis. Integrins are also known to regulate activation and
trafficking of receptor tyrosine kinases. However, the potential impact of integrins on cell fate induction remains largely unexplored.
In the model chordate, Ciona intestinalis, FGF/MapK signaling differentially activates the Ets1/2 transcription factor in founder cells
to induce cardiac cell fate. Previous work from our lab has found that integrin-mediated matrix adhesion is both necessary and
sufficient for asymmetric heart progenitor induction. To begin to address the role of integrin-mediated receptor trafficking in
asymmetric fate induction, we have focused on the predominant regulator of clathrin-independent receptor endocytosis, caveolin-1
(Cav1). We have found that over-expression of Ci-Cav1 is sufficient to rescue heart progenitor induction in founder cells where
adhesion has been disrupted. Furthermore, targeted expression of a dominant negative form of Ci-Cav1 in cardiac founder cells
significantly decreased heart progenitor induction. These results suggest that caveolin-rich membranes choreograph inductive
signaling in response to diverse extrinsic cues.
Program/Abstract # 319
Multiple Catenins Contribute to Development: Emerging Roles of Plakophilin-3 Catenin
Munoz, William; Miller, Rachel; Lee, Moonsup (MD Anderson Cancer Center, USA); Kloc, Malgorzata (The Methodist Hospital,
USA); McCrea, Pierre (MD Anderson Cancer Center, USA)
The catenin family has undergone a significant expansion during the evolution of vertebrates, resulting in varied functions that have
yet to be discerned or fully characterized. Catenins contain an Armadillo domain, bracketed by less conserved amino- and carboxyterminal
tails. The most prominent family member is beta-catenin, which acts at the adherens junction and in the nucleus, and is a key
player in both normal development and human disease. My work focuses upon Plakophilin-3 (Pkp3), a catenin that we hypothesize
provides key functions in differing cellular contexts. Members of the Pkps are found throughout the cell with little known about their
functions aside from that within desmosomal junctional plaques. Examples of Pkp3’s less understood activities include putative
functions in the cytosol, and further, my recent data intriguingly points to Pkp3 acting in the nucleus. I will present our
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